1,2-di(cyclic)substituted benzene compounds

ABSTRACT

A compound represented by the following general formula (1) or (100), a salt thereof or a hydrate of the foregoing has excellent cell adhesion inhibitory action or cell infiltration inhibitory action, and is useful as a therapeutic or prophylactic agent for various inflammatory diseases and autoimmune diseases associated with adhesion and infiltration of leukocytes, such as inflammatory bowel disease (particularly ulcerative colitis or Crohn&#39;s disease), irritable bowel syndrome, rheumatoid arthritis, psoriasis, multiple sclerosis, asthma and atopic dermatitis. 
     
       
         
         
             
             
         
       
         
         
           
             wherein R10 represents optionally substituted cycloalkyl, etc., R20-23 represent hydrogen, alkyl, alkoxy, etc., R30-32 represent hydrogen, alkyl, oxo, etc., and R40 represents optionally substituted alkyl, etc.

TECHNICAL FIELD

The present invention relates to 1,2-di(cyclic)substituted benzenecompounds which are useful as cell adhesion inhibitors or cellinfiltration inhibitors, as well as to their salts and to hydrates ofthe foregoing.

The present invention relates to 1,2-di(cyclic)substituted benzenecompounds which are useful as therapeutic or prophylactic agents forinflammatory diseases and autoimmune diseases, as well as to their saltsand to hydrates of the foregoing.

The invention further relates to 1,2-di(cyclic)substituted benzenecompounds which are useful as therapeutic or prophylactic agents forvarious diseases associated with adhesion and infiltration of leukocyte,such as inflammatory bowel disease (particularly ulcerative colitis orCrohn's disease), irritable bowel syndrome, rheumatoid arthritis,psoriasis, multiple sclerosis, asthma and atopic dermatitis, as well asto their salts and to hydrates of the foregoing.

BACKGROUND ART

Inflammatory reaction is accompanied by infiltration of leukocytes,typically neutrophils and lymphocytes, into inflammatory sites.

Infiltration of leukocytes is defined as migration of leukocytes such asneutrophils and lymphocytes out of vessels and into the surroundingtissues as a consequence of initiation and activation by cytokines,chemokines, lipids and complement to interact called “rolling” or“tethering” with vascular endothelial cells activated by cytokines suchas IL-1 or TNFα, followed by adhesion to the vascular endothelial cells.

As explained below, relationship between leukocyte adhesion orinfiltration and various inflammatory diseases and autoimmune diseaseswas reported. Such reports have raised the possibility that compoundshaving cell adhesion inhibitory action or cell infiltration inhibitoryaction may serve as therapeutic or prophylactic agents for suchdiseases.

-   (1) Therapeutic or prophylactic agents for inflammatory bowel    disease (ulcerative colitis, Crohn's disease and the like) (see    Non-patent documents 1, 2 and 3)-   (2) Therapeutic or prophylactic agents for irritable bowel syndrome    (see Non-patent document 4)-   (3) Therapeutic or prophylactic agents for rheumatoid arthritis (see    Non-patent document 5)-   (4) Therapeutic or prophylactic agents for psoriasis (see Non-patent    document 6)-   (5) Therapeutic or prophylactic agents for multiple sclerosis (see    Non-patent document 7)-   (6) Therapeutic or prophylactic agents for asthma (see Non-patent    document 8)-   (7) Therapeutic or prophylactic agents for atopic dermatitis (see    Non-patent document 9)

Thus, substances which inhibit cell adhesion or cell infiltration areexpected to be useful as therapeutic or prophylactic agents forinflammatory diseases and autoimmune diseases and as therapeutic orprophylactic agents for various diseases associated with adhesion andinfiltration of leukocytes, such as inflammatory bowel disease(particularly ulcerative colitis or Crohn's disease), irritable bowelsyndrome, rheumatoid arthritis, psoriasis, multiple sclerosis, asthmaand atopic dermatitis.

Compounds are also known which have anti-inflammatory action based oninhibition of adhesion of leukocyte and vascular endothelial cell, oranti-inflammatory action based on inhibition of leukocyte infiltration(these will hereinafter be referred to as cell adhesion inhibitors andcell infiltration inhibitors, respectively), such as the followingcompound:

(see Patent document 1).

However, the compounds represented by general formula (1) according tothe present invention are characterized by including a partial chemicalstructure having piperazine or piperidine at the ortho position of abenzene ring bonded to an aliphatic carbocyclic group such ascyclohexyl, therefore differ in their structures from the aforementionedcell adhesion inhibitors or cell infiltration inhibitors.

The known compound comprising a partial chemical structure havingpiperazine or piperidine at the ortho position of a benzene ring bondedto an aliphatic carbocyclic group such as cyclohexyl, as a chemicalstructural feature of the compounds represented by general formula (1)according to the present invention, is the compound represented by thefollowing formula:

(see Patent document 2).

However, the patent application discloses only its use as ananti-obesity agent and diabetes treatment based on the melanocortinreceptor agonistic activity of the compound, while it neither disclosesnor suggests its use as an anti-inflammatory agent based on inhibitoryaction of leukocyte adhesion or infiltration.

Other than the above compound, the compound represented by the followingformula:

is known (see Non-patent document 10, compound number 45).

-   [Patent document 1] WO 2002/018320-   [Patent document 2] WO 2002/059108-   [Non-patent document 1] Inflammatory Bowel Disease (N. Engl. J.    Med., 347:417-429 (2002))-   [Non-patent document 2] Natalizumab for active Crohn's disease (N.    Engl. J. Med., 348:24-32 (2003))-   [Non-patent document 3] Granulocyte adsorption therapy in active    period of ulcerative colitis (Japanese Journal of Apheresis    18:117-131 (1999))-   [Non-patent document 4] A role for inflammation in irritable bowel    syndrome (Gut., 51: i41-i44 (2002))-   [Non-patent document 5] Rheumatoid arthritis (Int. J. Biochem. Cell    Biol., 36:372-378 (2004))-   [Non-patent document 6] Psoriasis (Lancet, 361:1197-1204 (2003))-   [Non-patent document 7] New and emerging treatment options for    multiple sclerosis (Lancet Neurology, 2:563-566 (2003))-   [Non-patent document 8] The role of T lymphocytes in the    pathogenesis of asthma (J. Allergy Clin. Immunol., 111:450-463    (2003)-   [Non-patent document 9] The molecular basis of lymphocyte    recruitment to the skin (J. Invest. Dermatol., 121:951-962 (2003))-   [Non-patent document 10] Discovery of    2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimidazole (ABT-724), a    dopaminergic agent with a novel mode of action for the potential    treatment of erectile dysfunction (J. Med. Chem., 47: 3853-3864    (2004))

DISCLOSURE OF INVENTION

It is an object of the present invention to provide novel compoundshaving excellent cell adhesion inhibitory action and cell infiltrationinhibitory action, which are useful as therapeutic or prophylacticagents for various inflammatory diseases and autoimmune diseasesassociated with adhesion and infiltration of leukocytes, such asinflammatory bowel disease (particularly ulcerative colitis or Crohn'sdisease), irritable bowel syndrome, rheumatoid arthritis, psoriasis,multiple sclerosis, asthma and atopic dermatitis.

As a result of intensive research, the present inventors have discoveredthat 1,2-di(cyclic)substituted benzene compounds having the novelchemical structure described herein have excellent cell adhesioninhibitory action and cell infiltration inhibitory action, and areuseful as therapeutic or prophylactic agents for various inflammatorydiseases and autoimmune diseases associated with adhesion andinfiltration of leukocytes, such as inflammatory bowel disease(particularly ulcerative colitis or Crohn's disease), irritable bowelsyndrome, rheumatoid arthritis, psoriasis, multiple sclerosis, asthmaand atopic dermatitis, and the present invention was completed on thebasis of this discovery.

Specifically, the invention is a compound having the following generalformula (1) or (100), a salt thereof or a hydrate of the foregoing:

Also, the invention is a medicament comprising the compound having theaforementioned general formula (1) or (100), the salt thereof or thehydrate of the foregoing.

Further, the invention is a cell adhesion inhibitor and a cellinfiltration inhibitor comprising the compounds having theaforementioned general formula (1) or (100), the salt thereof or thehydrate of the foregoing.

Still further, the invention is a therapeutic or prophylactic agent forinflammatory diseases or autoimmune diseases, comprising the compoundhaving the aforementioned general formula (1) or (100), the salt thereofor the hydrate of the foregoing.

Particularly, the invention is a therapeutic or prophylactic agent forinflammatory bowel disease (particularly ulcerative colitis or Crohn'sdisease), irritable bowel syndrome, rheumatoid arthritis, psoriasis,multiple sclerosis, asthma, atopic dermatitis and the like, comprisingthe compound having the aforementioned general formula (1) or (100), thesalt thereof or the hydrate of the foregoing.

Still particularly, the invention is use of the compound having theaforementioned general formula (1) or (100), the salt thereof or thehydrate of the foregoing for the manufacture of a medicament.

In formulas (1) and (100) above,

R10 represents 5- to 10-membered cycloalkyl optionally substituted witha substituent selected from Group A1 or 5- to 10-membered cycloalkenyloptionally substituted with a substituent selected from Group A1,

R20, R21, R22 and R23 may be the same or different and each representshydrogen, hydroxyl, halogen, cyano, C2-7 alkylcarbonyl, nitro, amino,mono(C1-6 alkyl)amino, di(C1-6 alkyl)amino, C1-6 alkyl optionallysubstituted with a substituent selected from Group B1, C1-6 alkoxyoptionally substituted with a substituent selected from Group B1, a 4-to 8-membered heterocyclic group optionally substituted with asubstituent selected from Group C1, or a 5- to 10-membered heteroarylring group optionally substituted with a substituent selected from GroupC1,

R30, R31 and R32 may be the same or different and each representshydrogen, hydroxyl, halogen, cyano, carboxyl, C1-6 alkyl, C1-6 alkoxy orC2-7 alkoxycarbonyl, or

two of R30, R31 and R32 bond together to form oxo (═O) or methylene(—CH₂—) and the other represents hydrogen, hydroxyl, halogen, cyano,carboxyl, C1-6 alkyl, C1-6 alkoxy or C2-7 alkoxycarbonyl,

R40 represents C1-10 alkyl optionally substituted with a substituentselected from Group D1,3- to 8-membered cycloalkyl optionallysubstituted with a substituent selected from Group E1, a 4- to8-membered heterocyclic group optionally substituted with a substituentselected from Group E1, C2-7 alkenyl optionally substituted with asubstituent selected from Group F1, C2-7 alkynyl optionally substitutedwith a substituent selected from Group F1, C2-7 alkylcarbonyl optionallysubstituted with a substituent selected from Group G1, mono(C1-6alkyl)aminocarbonyl, 4- to 8-membered heterocyclic carbonyl, C2-7alkoxycarbonyl or C1-6 alkylsulfonyl,

n represents an integer of 0, 1 or 2,

X1 represents CH or nitrogen,

Group A1 represents a group consisting of hydroxyl, halogen, cyano, C1-6alkoxy, phenyl optionally substituted with a substituent selected fromGroup C1, C1-6 alkyl, C1-6 haloalkyl and C2-7 alkylene, where C2-7alkylene is permissible only in the case that a spiro union is formedtogether with the substituted 5- to 10-membered cycloalkyl or thesubstituted 5- to 10-membered cycloalkenyl,

Group B1 represents a group consisting of halogen, C2-7 alkoxycarbonyland carboxyl,

Group C1 represents a group consisting of cyano, halogen, C1-6 alkyl andC1-6 alkoxy,

Group D1 represents a group consisting of hydroxyl, halogen, cyano, C1-6alkoxy, C1-6 alkylthio, C1-6 alkylsulfonyl, C1-6 alkylsulfinyl,mono(C1-6 alkyl)amino, di(C1-6 alkyl)amino, C2-7 alkylcarbonylamino, 3-to 8-membered cycloalkyl optionally substituted with a substituentselected from Group H1, C2-7 alkoxycarbonyl, carboxyl, a 4- to8-membered heterocyclic group, a 5- to 10-membered heteroaryl ringgroup, a 6- to 10-membered aryl ring group, C2-7 alkylcarbonyl, a 6- to10-membered aryl ring carbonyl group, aminocarbonyl, mono(C1-6alkyl)aminocarbonyl optionally substituted with halogen, mono(3- to8-membered cycloalkyl)aminocarbonyl, mono(C2-7alkoxyalkyl)aminocarbonyl, di(C1-6 alkyl)aminocarbonyl, mono(5- to10-membered heteroaryl ring)aminocarbonyl, 4- to 8-membered heterocycliccarbonyl optionally substituted with C 1-6 alkyl, and 5- to 10-memberedheteroaryl ring carbonyl,

Group E1 represents a group consisting of halogen, C1-6 alkoxy, oxo (═O)and C1-6 alkyl,

Group F1 represents a group consisting of halogen and C1-6 alkoxy,

Group G1 represents a group consisting of 3- to 8-membered cycloalkyl,and

Group H1 represents a group consisting of hydroxyl, C1-6 haloalkyl, C1-6alkyl, C2-7 alkoxyalkyl, mono(C1-6 alkyl)aminocarbonyl, di(C1-6alkyl)aminocarbonyl, C2-7 alkoxycarbonyl, carboxyl and C2-7 cyanoalkyl.

A compound represented by the formula

is excepted from the compound represented by the formula (1).

As examples of the “cycloalkyl” of the “cycloalkyl optionallysubstituted with a substituent selected from Group A1” for R10 above,there may be mentioned cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclononyl or cyclodecyl, among which cyclopentyl, cyclohexyl,cycloheptyl or cyclooctyl is preferred, and cyclohexyl is particularlypreferred.

The “cycloalkenyl” of the “cycloalkenyl optionally substituted with asubstituent selected from Group A1” for R10 above may have multipledouble bonds, and as examples there may be mentioned cyclopentenyl(1-cyclopentenyl, 2-cyclopentenyl or 3-cyclopentenyl), cyclohexenyl(1-cyclohexenyl, 2-cyclohexenyl or 3-cyclohexenyl), cycloheptenyl(1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl or 4-cycloheptenyl),cyclooctenyl (1-cyclooctenyl, 2-cyclooctenyl, 3-cyclooctenyl or4-cyclooctenyl), cyclononenyl (1-cyclononenyl, 2-cyclononenyl,3-cyclononenyl, 4-cyclononenyl or 5-cyclononenyl) or cyclodecenyl(1-cyclodecenyl, 2-cyclodecenyl, 3-cyclodecenyl, 4-cyclodecenyl or5-cyclodecenyl), among which cyclopentenyl, cyclohexenyl, cycloheptenylor cyclooctenyl is preferred, cyclohexenyl is more preferred, and1-cyclohexenyl is most preferred.

As examples of the “halogen” for R20, R21, R22 and R23 above, there maybe mentioned fluorine, chlorine, bromine or iodine, among which bromine,fluorine or chlorine is preferred.

The “C2-7 alkylcarbonyl” for R20, R21, R22 and R23 above is a carbonylgroup having the “C1-6 alkyl” described below bonded thereto, and asexamples there may be mentioned straight-chain or branched-chain groupssuch as acetyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl,n-butylcarbonyl, isobutylcarbonyl, s-butylcarbonyl, t-butylcarbonyl,pentylcarbonyl, isopentylcarbonyl, 2-methylbutylcarbonyl,neopentylcarbonyl, 1-ethylpropylcarbonyl, hexylcarbonyl,isohexylcarbonyl, 4-methylpentylcarbonyl, 3-methylpentylcarbonyl,2-methylpentylcarbonyl, 1-methylpentylcarbonyl,3,3-dimethylbutylcarbonyl, 2,2-dimethylbutylcarbonyl,1,1-dimethylbutylcarbonyl, 1,2-dimethylbutylcarbonyl,1,3-dimethylbutylcarbonyl, 2,3-dimethylbutylcarbonyl,1-ethylbutylcarbonyl or 2-ethylbutylcarbonyl, among which C2-5 groupsare preferred, and acetyl or ethylcarbonyl is particularly preferred.

As examples of the “mono(C1-6 alkyl)amino” for R20, R21, R22 and R23above, there may be mentioned straight-chain or branched-chain groupssuch as methylamino, ethylamino, propylamino, isopropylamino,butylamino, isobutylamino, s-butylamino, t-butylamino, pentylamino,isopentylamino, 2-methylbutylamino, neopentylamino, 1-ethylpropylamino,hexylamino, isohexylamino, 4-methylpentylamino, 3-methylpentylamino,2-methylpentylamino, 1-methylpentylamino, 3,3-dimethylbutylamino,2,2-dimethylbutylamino, 1,1-dimethylbutylamino, 1,2-dimethylbutylamino,1,3-dimethylbutylamino, 2,3-dimethylbutylamino, 1-ethylbutylamino or2-ethylbutylamino, among which methylamino or ethylamino is preferred,and methylamino is particularly preferred.

The “di(C1-6 alkyl)amino” for R20, R21, R22 and R23 above may be eithersymmetric or asymmetric, and as examples there may be mentionedstraight-chain or branched-chain groups such as dimethylamino,methylethylamino, diethylamino, methylpropylamino, ethylpropylamino,dipropylamino, diisopropylamino, dibutylamino, diisobutylamino,di(s-butyl)amino, di(t-butyl)amino, methylpentylamino, dipentylamino,diisopentylamino, di(2-methylbutyl)amino, di(neopentyl)amino,di(1-ethylpropyl)amino, dihexylamino, methylisohexylamino,diisohexylamino, di(4-methylpentyl)amino, di(3-methylpentyl)amino,di(2-methylpentyl)amino, di(1-methylpentyl)amino,di(3,3-dimethylbutyl)amino, di(2,2-dimethylbutyl)amino,di(1,1-dimethylbutyl)amino, di(1,2-dimethylbutyl)amino,di(1,3-dimethylbutyl)amino, di(2,3-dimethylbutyl)amino,di(1-ethylbutyl)amino or di(2-ethylbutyl)amino, among whichdimethylamino, methylethylamino or diethylamino is preferred, anddimethylamino is particularly preferred.

As examples of the “C1-6 alkyl” of the “C1-6 alkyl optionallysubstituted with a substituent selected from Group B1” for R20, R21, R22and R23 above, there may be mentioned straight-chain or branched-chaingroups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,s-butyl, t-butyl, n-pentyl, isopentyl, s-pentyl, t-pentyl,2-methylbutyl, 1-methylbutyl, 2-methylbutyl, neopentyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl,isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl,1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl,1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1-ethylbutyl,2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl,1-ethyl-1-methylpropyl or 1-ethyl-2-methylpropyl, among which C1-4groups are preferred, methyl, ethyl or t-butyl is more preferred, andmethyl is most preferred.

As examples of the “C1-6 alkoxy” of the “C1-6 alkoxy optionallysubstituted with a substituent selected from Group B1” for R20, R21, R22and R23 above, there may be mentioned straight-chain or branched-chaingroups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,s-butoxy, t-butoxy, pentoxy, isopentoxy, 2-methylbutoxy, neopentoxy,hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy,3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy,1,2-dimethylbutoxy, 1,3-dimethylbutoxy or 2,3-dimethylbutoxy, amongwhich methoxy, ethoxy, propoxy or isopropoxy is preferred, methoxy orethoxy is more preferred, and methoxy is most preferred.

The “4- to 8-membered heterocyclic group” of the “4- to 8-memberedheterocyclic group optionally substituted with a substituent selectedfrom Group C1” for R20, R21, R22 and R23 above is a monovalent groupobtained by removing one hydrogen from any desired position of a “4- to8-membered heterocycle” as described below.

The “4- to 8-membered heterocycle” is a non-aromatic ring (eithercompletely saturated or partially unsaturated) having 4-8 atoms formingthe ring and containing one or more heteroatoms among the atoms formingthe ring, and as examples there may be mentioned an azetidine ring, apyrrolidine ring, a piperidine ring, an azepane ring, an azocane ring, atetrahydrofuran ring, a tetrahydropyran ring, a tetrahydrothiopyranring, a morpholine ring, a thiomorpholine ring, a piperazine ring, adiazepane ring, a thiazolidine ring, an isoxazolidine ring, animidazolidine ring, a pyrazolidine ring, a dioxane ring, a 1,3-dioxolanering, an oxathiane ring, a dithiane ring, a pyran ring, a dihydropyranring, a pyrroline ring, a pyrazoline ring, an oxazoline ring, animidazoline ring or a thiazoline ring.

Preferable “4- to 8-membered heterocyclic groups” are completelysaturated 4- to 8-membered heterocyclic groups, completely saturated 4-to 8-membered heterocyclic groups derived by eliminating hydrogen linkedto nitrogen constituting the ring are more preferred, pyrrolidin-1-yl,azetidin-1-yl, thiomorpholin-4-yl, piperidin-1-yl or morpholin-4-yl isfurther preferred, and pyrrolidin-1-yl, piperidin-1-yl or morpholin-4-ylis most preferred.

The “5- to 10-membered heteroaryl ring group” of the “5- to 10-memberedheteroaryl ring group optionally substituted with a substituent selectedfrom Group C1” for R20, R21, R22 and R23 above is a monovalent groupobtained by removing one hydrogen from any desired position of a “5- to10-membered heteroaryl ring” as described below.

The “5- to 10-membered heteroaryl ring” is an aromatic ring having 5-10atoms forming the ring and containing one or more heteroatoms among theatoms forming the ring (with regard to fused rings, at least one of therings are aromatic), and as examples there may be mentioned a pyridinering, a thiophene ring, a furan ring, a pyrrole ring, a oxazole ring, aisoxazole ring, a thiazole ring, a thiadiazole ring, an isothiazolering, an imidazole ring, a triazole ring, a tetrazole ring, a pyrazolering, a furazan ring, a thiadiazole ring, an oxadiazole ring, apyridazine ring, a pyrimidine ring, a pyrazine ring, a triazine ring, anindole ring, an isoindole ring, an indazole ring, a quinoline ring, anisoquinoline ring, a cinnoline ring, a quinazoline ring, a quinoxalinering, a naphthylidine ring, a phthalazine ring, a purine ring, apteridine ring, a thienofuran ring, an imidazothiazole ring, abenzofuran ring, a benzothiophene ring, a benzoxazole ring, abenzothiazole ring, a benzothiadiazole ring, a benzimidazole ring, animidazopyridine ring, a pyrrolopyridine ring, a pyrrolopyrimidine ring,a pyridopyrimidine ring, a coumarane ring, a chromene ring, a chromanring, a isochroman ring, a indoline ring or a isoindoline ring.Preferable “5- to 10-membered heteroaryl ring groups” are 5- to6-membered groups, an isoxazole ring group, an oxadiazole ring group, atetrazole ring group, a pyridine ring group, a thiazole ring group or athiophen ring group is more preferred, and a pyridine ring group, athiazole ring group, a thiophen ring group or a tetrazole ring group isparticularly preferred.

As the “halogen” for R30, R31 and R32 above there may be mentioned thesame ones listed above, among which fluorine or chlorine is preferred.

As examples of the “C1-6 alkyl” for R30, R31 and R32 above there may bementioned the same ones listed above, among which C1-4 groups arepreferred, and methyl is particularly preferred.

As examples of the “C1-6 alkoxy” for R30, R31 and R32 above there may bementioned the same ones listed above, among which C1-4 groups arepreferred, and methoxy is particularly preferred.

The “C2-7 alkoxycarbonyl” for R30, R31 and R32 above is a carbonyl grouphaving the aforementioned “C1-6 alkoxy” bonded thereto, and as examplesthere may be mentioned straight-chain or branched-chain groups such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl,pentoxycarbonyl, isopentoxycarbonyl, 2-methylbutoxycarbonyl,neopentoxycarbonyl, hexyloxycarbonyl, 4-methylpentoxycarbonyl,3-methylpentoxycarbonyl, 2-methylpentoxycarbonyl,3,3-dimethylbutoxycarbonyl, 2,2-dimethylbutoxycarbonyl,1,1-dimethylbutoxycarbonyl, 1,2-dimethylbutoxycarbonyl,1,3-dimethylbutoxycarbonyl or 2,3-dimethylbutoxycarbonyl, among whichmethoxycarbonyl or ethoxycarbonyl is preferred.

As examples of the “C1-10 alkyl” of the “C1-10 alkyl optionallysubstituted with a substituent selected from Group D1” for R40 abovethere may be mentioned, in addition to the aforementioned C1-6 alkyl,straight-chain or branched-chain C7-C10 alkyl groups such as heptyl,3-methylhexyl, octyl, nonyl or decyl, among which C1-6 alkyl groups arepreferred, and methyl, ethyl, propyl, isopropyl, isobutyl, butyl orpentyl is particularly preferred.

As examples of the “3- to 8-membered cycloalkyl” of the “3- to8-membered cycloalkyl optionally substituted with a substituent selectedfrom Group E1” for R40 above, there may be mentioned cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, amongwhich cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl ispreferred, and cyclobutyl, cyclopentyl or cyclohexyl is particularlypreferred.

As examples of the “4- to 8-membered heterocyclic group” of the “4- to8-membered heterocyclic group optionally substituted with a substituentselected from Group E1” for R40 above, there may be mentioned the sameones listed above, among which a pyrrolidine ring group, a piperidinering group, a tetrahydrothiopyran ring group or a tetrahydropyran ringgroup is preferred.

The “C2-7 alkenyl” of the “C2-7 alkenyl optionally substituted with asubstituent selected from Group F1” for R40 above is straight-chain orbranched-chain alkenyl groups of 2 to 7 carbon which may contain 1 or 2double bonds, and as examples there may be mentioned ethenyl,1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl,2-methyl-1-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 1-hexenyl,1,6-hexadienyl or 1-heptenyl, among which C2-5 groups are preferred, and2-propenyl or 2-methyl-2-propenyl is particularly preferred.

The “C2-7 alknyl” of the “C2-7 alkynyl optionally substituted with asubstituent selected from Group F1” for R40 above is straight-chain orbranched-chain alkynyl groups of 2 to 7 carbon which may contain 1 or 2triple bonds, and as examples there may be mentioned ethynyl,1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butenyl, 1-pentynyl,1-hexynyl, 1,6-hexadienyl or 1-heptynyl, among which C2-5 groups arepreferred, and 2-butynyl or 2-propynyl is particularly preferred.

As examples of the “C2-7 alkylcarbonyl” of “C2-7 alkylcarbonyloptionally substituted with a substituent selected from Group G1” forR40 above, there may be mentioned the same ones listed above, amongwhich C2-5 groups are preferred, and acetyl or propylcarbonyl isparticularly preferred.

The “mono(C1-6 alkyl)aminocarbonyl” for R40 above is a carbonyl grouphaving the aforementioned “mono(C1-6 alkyl)amino” bonded thereto, and asexamples there may be mentioned straight-chain or branched-chain groupssuch as methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl,isopropylaminocarbonyl, butylaminocarbonyl, isobutylaminocarbonyl,s-butylaminocarbonyl, t-butylaminocarbonyl, pentylaminocarbonyl,isopentylaminocarbonyl, 2-methylbutylaminocarbonyl,neopentylaminocarbonyl, 1-ethylpropylaminocarbonyl, hexylaminocarbonyl,isohexylaminocarbonyl, 4-methylpentylaminocarbonyl,3-methylpentylaminocarbonyl, 2-methylpentylaminocarbonyl,1-methylpentylaminocarbonyl, 3,3-dimethylbutylaminocarbonyl,2,2-dimethylbutylaminocarbonyl, 1,1-dimethylbutylaminocarbonyl,1,2-dimethylbutylaminocarbonyl, 1,3-dimethylbutylaminocarbonyl,2,3-dimethylbutylaminocarbonyl, 1-ethylbutylaminocarbonyl or2-ethylbutylaminocarbonyl, among which C2-5 groups (total number ofcarbon) are preferred and ethylaminocarbonyl is particularly preferred.

The “4- to 8-membered heterocyclic carbonyl” for R40 above is a carbonylgroup having the aforementioned “4- to 8-membered heterocyclic group”bonded thereto, among which piperidin-1-ylcarbonyl ormorpholin-4-ylcarbonyl is preferred.

As examples of “C2-7 alkoxycarbonyl” for R40 above there may bementioned the same one listed above, among which methoxycarbonyl orethoxycarbonyl is preferred.

The “C1-6 alkylsulfonyl” for R40 above is a sulfonyl group having theaforementioned “C1-6 alkyl” bonded thereto, as examples there may bementioned straight-chain or branched-chain groups such asmethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl,butylsulfonyl, isobutylsulfonyl, s-butylsulfonyl, t-butylsulfonyl,pentylsulfonyl, isopentylsulfonyl, 2-methylbutylsulfonyl,neopentylsulfonyl, 1-ethylpropylsulfonyl, hexylsulfonyl,isohexylsulfonyl, 4-methylpentylsulfonyl, 3-methylpentylsulfonyl,2-methylpentylsulfonyl, 1-methylpentylsulfonyl,3,3-dimethylbutylsulfonyl, 2,2-dimethylbutylsulfonyl,1,1-dimethylbutylsulfonyl, 1,2-dimethylbutylsulfonyl,1,3-dimethylbutylsulfonyl, 2,3-dimethylbutylsulfonyl,1-ethylbutylsulfonyl or 2-ethylbutylsulfonyl, among which propylsulfonylis preferred.

As examples of the “halogen” of Group A1, there may be mentioned thesame ones listed above, among which bromine, fluorine or chlorine ispreferred.

As examples of the “C1-6 alkoxy” of Group A1, there may be mentioned thesame ones listed above, among which C1-4 groups are preferred, andmethoxy is particularly preferred.

As examples of the “C1-6 alkyl” of Group A1 and Group A2, there may bementioned the same ones listed above, among which C1-4 groups arepreferred, and methyl, ethyl, n-butyl or t-butyl is particularlypreferred.

The “C1-6 haloalkyl” of Group A1 and Group A2 is aforementioned “C1-6alkyl” having 1 to 6 aforementioned “halogen” bonded thereto, asexamples there may be mentioned straight-chain or branched-chain alkylgroups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl,1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl,2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl,1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,3-dimethylbutyl, 1-ethylbutyl or 2-ethylbutyl, having fluorine orchlorine bonded thereto, among which C1-4 alkyl having 1 to 3 fluorineor chlorine bonded thereto is preferred, and trifluoromethyl isparticularly preferred.

As examples of the “C2-7 alkylene”, where C2-7 alkylene is permissibleonly in the case that a spiro union is formed together with thesubstituted 5- to 10-membered cycloalkyl or the substituted 5- to10-membered cycloalkenyl, of Group A1 and Group A2, there may bementioned straight-chain or branched-chain groups such as 1,2-ethylene,trimethylene, propylene, ethylethylene, tetramethylene, pentamethylene,hexamethylene or heptamethylene, among which 1,2-ethylene,tetramethylene or pentamethylene is preferred.

As examples of the “halogen” of Group B1, there may be mentioned thesame ones listed above, among which fluorine or chlorine is preferred.

As examples of the “C2-7 alkoxycarbonyl” of Group B1, there may bementioned the same ones listed above, among which methoxycarbonyl orethoxycarbonyl is preferred.

As examples of the “halogen” of Group C1, there may be mentioned thesame ones listed above, among which bromine, fluorine or chlorine ispreferred.

As examples of the “C1-6 alkyl” of Group C1 and Group C2, there may bementioned the same ones listed above, among which C1-4 groups arepreferred, and methyl is particularly preferred.

As examples of the “C1-6 alkoxy” of Group C1 and Group C2, there may bementioned the same ones listed above, among which C1-4 groups arepreferred, and methoxy, ethoxy or isopropoxy is particularly preferred.

As examples of the “halogen” of Group D1 and Group D2, there may bementioned the same ones listed above, among which fluorine or chlorineis preferred.

As examples of the “C1-6 alkoxy” of Group D1 and Group D2, there may bementioned the same ones listed above, among which C1-4 groups arepreferred, and methoxy or ethoxy is particularly preferred.

The “C1-6 alkylthio” of Group D1 is a thio group having theaforementioned “C1-6 alkyl” bonded thereto, and as examples there may bementioned straight-chain or branched-chain groups such as methylthio,ethylthio, propylthio, isopropylthio, butylthio, isobutylthio,s-butylthio, t-butylthio, pentylthio, isopentylthio, 2-methylbutylthio,neopentylthio, 1-ethylpropylthio, hexylthio, isohexylthio,4-methylpentylthio, 3-methylpentylthio, 2-methylpentylthio,1-methylpentylthio, 3,3-dimethylbutylthio, 2,2-dimethylbutylthio,1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutylthio,2,3-dimethylbutylthio, 1-ethylbutylthio or 2-ethylbutylthio, among whichC1-4 groups are preferred and methylthio or ethylthio is particularlypreferred.

As examples of the “C1-6 alkylsulfonyl” of Group D1 there may bementioned the same ones listed above, among which C1-4 groups arepreferred, and methylsulfonyl or ethylsulfonyl is particularlypreferred.

The “C1-6 alkyl sulfinyl” of Group D1 is a sulfinyl group having theaforementioned “C1-6 alkyl” bonded thereto, as examples there may bementioned straight-chain or branched-chain groups such asmethylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl,butylsulfinyl, isobutylsulfinyl, s-butylsulfinyl, t-butylsulfinyl,pentylsulfinyl, isopentylsulfinyl, 2-methylbutylsulfinyl,neopentylsulfinyl, 1-ethylpropylsulfinyl, hexylsulfinyl,isohexylsulfinyl, 4-methylpentylsulfinyl, 3-methylpentylsulfinyl,2-methylpentylsulfinyl, 1-methylpentylsulfinyl,3,3-dimethylbutylsulfinyl, 2,2-dimethylbutylsulfinyl,1,1-dimethylbutylsulfinyl, 1,2-dimethylbutylsulfinyl,1,3-dimethylbutylsulfinyl, 2,3-dimethylbutylsulfinyl,1-ethylbutylsulfinyl or 2-ethylbutylsulfinyl, among which C1-4 groupsare preferred, and methylsulfinyl or ethylsulfinyl is particularlypreferred.

As examples of the “mono(C1-6 alkyl)amino” of Group D1 there may bementioned the same ones listed above, among which methylamino orethylamino is preferred, and methylamino is particularly preferred.

As examples of the “di(C1-6 alkyl)amino” of Group D1 there may bementioned the same ones listed above, among which dimethylamino,methylethylamino or diethylamino is preferred, and dimethylamino isparticularly preferred.

The “C2-7 alkylcarbonylamino” of Group D1 is an amino group having theaforementioned “C2-7 alkylcarbonyl” bonded thereto, and as examplesthere may be mentioned straight-chain or branched-chain groups such asacetylamino, ethylcarbonylamino, n-propylcarbonyl amino,isopropylcarbonylamino, n-butylcarbonylamino, isobutylcarbonylamino,s-butylcarbonylamino, t-butylcarbonylamino, pentylcarbonylamino,isopentylcarbonylamino, 2-methylbutylcarbonylamino,neopentylcarbonylamino, 1-ethylpropylcarbonylamino, hexylcarbonylamino,isohexylcarbonylamino, 4-methylpentylcarbonylamino,3-methylpentylcarbonylamino, 2-methylpentylcarbonylamino,1-methylpentylcarbonylamino, 3,3-dimethylbutylcarbonylamino,2,2-dimethylbutylcarbonylamino, 1,1-dimethylbutylcarbonylamino,1,2-dimethylbutylcarbonylamino, 1,3-dimethylbutylcarbonylamino,2,3-dimethylbutylcarbonylamino, 1-ethylbutylcarbonylamino or2-ethylbutylcarbonylamino, among which amino groups having C2-5alkylcarbonyl bonded thereto are preferred, and acetylamino orethylcarbonylamino is particularly preferred.

As examples of the “3- to 8-membered cycloalkyl” of “3- to 8-memberedcycloalkyl optionally substituted with a substituent selected from GroupH1” of Group D1 and the “3- to 8-membered cycloalkyl” of Group D2, theremay be mentioned the same ones listed above, among which cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl is preferred, cyclopropyl orcyclobutyl is more preferred, and cyclopropyl is most preferred.

As examples of the “C2-7 alkoxycarbonyl” of Group D1 there may bementioned the same ones listed above, among which methoxycarbonyl orethoxycarbonyl is preferred.

As examples of the “4- to 8-membered heterocyclic group” of Group D1 andGroup D2, there may be mentioned the same ones listed above, among whicha tetrahydropyran ring group or a tetrahydrofuran ring group ispreferred, and tetrahydropyran-4-yl is particularly preferred.

As examples of the “5- to 10-membered heteroaryl ring group” of GroupD1, there may be mentioned the same ones listed above, among whichfuryl, thienyl, pyridyl, pyrazyl, pyrimidinyl or pyridazinyl ispreferred, and furyl, thienyl or pyridyl is particularly preferred.

The “6- to 10-membered aryl ring group” of Group D1 is aromatichydrocarbon ring group of 6 to 10 carbon (with regard to fused rings, atleast one of the rings are aromatic), as examples there may be mentionedphenyl, 1-naphthyl, 2-naphthyl, indenyl, indanyl, azulenyl orheptalenyl, among which phenyl, 1-naphthyl or 2-naphthyl is preferred,and phenyl is particularly preferred.

As examples of the “C2-7 alkylcarbonyl” of Group D1 and Group D2, theremay be mentioned the same ones listed above, among which C2-5 groups arepreferred, and acetyl or ethylcarbonyl is particularly preferred.

The “6- to 10-membered aryl ring carbonyl group” of Group D1 is acarbonyl group having the aforementioned “6- to 10-membered aryl ringgroup” bonded thereto, and as examples there may be mentioned benzoyl,1-naphthoyl, 2-naphthoyl, indenylcarbonyl, indanylcarbonyl,azulenylcarbonyl or heptalenylcarbonyl, among which benzoyl, 1-naphthoylor 2-naphthoyl is preferred, and benzoyl is particularly preferred.

As examples of the “mono(C1-6 alkyl)aminocarbonyl” of “mono(C1-6alkyl)aminocarbonyl optionally substituted with halogen” for Group D1and the “mono(C1-6 alkyl)aminocarbonyl” of Group D2, there may bementioned the same ones listed above, among which C2-5 groups arepreferred, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl,isopropylaminocarbonyl or butylaminocarbonyl is more preferred, andmethylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl orisopropylaminocarbonyl is most preferred.

As examples of the “mono(3- to 8-membered cycloalkyl)aminocarbonyl” ofGroup D1, there may be mentioned cyclopropylaminocarbonyl,cyclobutylaminocarbonyl, cyclopentylaminocarbonyl,cyclohexylaminocarbonyl, cycloheptylaminocarbonyl orcyclooctylaminocarbonyl, among which cyclopropylaminocarbonyl,cyclobutylaminocarbonyl, cyclopentylaminocarbonyl orcyclohexylaminocarbonyl is preferred, and cyclopropylaminocarbonyl isparticularly preferred.

The “mono(C2-7 alkoxyalkyl)aminocarbonyl” of Group D1 is anaminocarbonyl group having “C2-7 alkoxyalkyl” bonded thereto, where“C2-7 alkoxyalkyl” is aforementioned “C1-6 alkyl” having theaforementioned “C1-6 alkoxy” bonded thereto in the range of C2-7. Asexamples of “mono(C2-7 alkoxyalkyl)aminocarbonyl” there may be mentionedmethoxymethylaminocarbonyl, methoxyethylaminocarbonyl,ethoxyethylaminocarbonyl, methoxypropylaminocarbonyl orpropoxyethylaminocarbonyl, among which methoxyethylaminocarbonyl ispreferred.

The “di(C1-6 alkyl)aminocarbonyl” of Group D1 and Group D2 is a carbonylgroup having the aforementioned “di(C1-6 alkyl)amino” bonded thereto,and as examples there may be mentioned straight-chain or branched-chaingroups such as dimethylaminocarbonyl, methylethylaminocarbonyl,diethylaminocarbonyl, methylpropylaminocarbonyl,ethylpropylaminocarbonyl, dipropylaminocarbonyl,diisopropylaminocarbonyl, dibutylaminocarbonyl, diisobutylaminocarbonyl,di(s-butyl)aminocarbonyl, di(t-butyl)aminocarbonyl,methylpentylaminocarbonyl, dipentylaminocarbonyl,diisopentylaminocarbonyl, di(2-methylbutyl)aminocarbonyl,di(neopentyl)aminocarbonyl, di(1-ethylpropyl)aminocarbonyl,dihexylaminocarbonyl, methylisohexylaminocarbonyl,diisohexylaminocarbonyl, di(4-methylpentyl)aminocarbonyl,di(3-methylpentyl)aminocarbonyl, di(2-methylpentyl)aminocarbonyl,di(1-methylpentyl)aminocarbonyl, di(3,3-dimethylbutyl)aminocarbonyl,di(2,2-dimethylbutyl)aminocarbonyl, di(1,1-dimethylbutyl)aminocarbonyl,di(1,2-dimethylbutyl)aminocarbonyl, di(1,3-dimethylbutyl)aminocarbonyl,di(2,3-dimethylbutyl)aminocarbonyl, di(1-ethylbutyl)aminocarbonyl ordi(2-ethylbutyl)aminocarbonyl, among which dimethylaminocarbonyl,methylethylaminocarbonyl or diethylaminocarbonyl is preferred, anddimethylaminocarbonyl is particularly preferred.

The “mono(5- to 10-membered heteroaryl ring)aminocarbonyl” of Group D1is a group obtained by substituting one hydrogen of aminocarbonyl(carbamoyl) with the aforementioned “5- to 10-membered heteroaryl ring”group, where as examples of the “5- to 10-membered heteroaryl ring”there may be mentioned a pyridine ring, a thiophene ring, a furan ring,a pyrrole ring, a oxazole ring, a isoxazole ring, a thiazole ring, athiadiazole ring, an isothiazole ring, an imidazole ring, a triazolering, a tetrazole ring, a pyrazole ring, a furazan ring, a thiadiazolering, an oxadiazole ring, a pyridazine ring, a pyrimidine ring, apyrazine ring, a triazine ring, an indole ring, an isoindole ring, anindazole ring, a quinoline ring, an isoquinoline ring, a cinnoline ring,a quinazoline ring, a quinoxaline ring, a naphthylidine ring, aphthalazine ring, a purine ring, a pteridine ring, a thienofuran ring,an imidazothiazole ring, a benzofuran ring, a benzothiophene ring, abenzoxazole ring, a benzothiazole ring, a benzothiadiazole ring, abenzimidazole ring, an imidazopyridine ring, a pyrrolopyridine ring, apyrrolopyrimidine ring, a pyridopyrimidine ring, a coumarane ring, achromene ring, a chroman ring, a isochroman ring, a indoline ring or aisoindoline ring. Preferable mono(5- to 10-membered heteroarylring)aminocarbonyl is pyridine-2-ylaminocarbonyl.

As examples of the “4- to 8-membered heterocyclic carbonyl” of “4- to8-membered heterocyclic carbonyl optionally substituted with C1-6 alkyl”for Group D1 and “4- to 8-membered heterocyclic carbonyl” of Group D2,there may be mentioned the same ones listed above, among whichpyrrolidin-1-ylcarbonyl, azepan-1-ylcarbonyl, azocan-1-ylcarbonyl,piperidin-1-ylcarbonyl or morpholin-4-ylcarbonyl is preferred, andpyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl ormorpholin-4-ylcarbonyl is particularly preferred.

The “5- to 10-membered heteroaryl ring carbonyl” of Group D1 is acarbonyl group having the aforementioned “5- to 10-membered heteroarylring group” bonded thereto.

The “5-membered heteroaryl ring group” of Group D2 is a group, thenumber of atoms constituting the ring is 5 in the aforementioned “5- to10-membered heteroaryl ring group”, as examples there may be mentionedthienyl, furyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl,isothiazolyl, imidazolyl, triazolyl, pyrazolyl, furazanyl oroxadiazolyl, among which thienyl or furyl is preferred.

As examples of the “halogen” of Group E1 there may be mentioned the sameones listed above, among which bromine, fluorine or chlorine ispreferred.

As examples of the “C1-6 alkoxy” of Group E1 there may be mentioned thesame ones listed above, among which C1-4 groups are preferred, andmethoxy is particularly preferred.

As examples of the “C1-6 alkyl” of Group E1 there may be mentioned thesame ones listed above, among which C1-4 groups are preferred, andmethyl is particularly preferred.

As examples of the “halogen” of Group F1 there may be mentioned the sameones listed above, among which fluorine or chlorine is preferred.

As examples of the “C1-6 alkoxy” of Group F1 there may be mentioned thesame ones listed above, among which C1-4 groups are preferred, andmethoxy is particularly preferred.

As examples of the “3- to 8-membered cycloalkyl” of Group G1 there maybe mentioned the same ones listed above, among which cyclohexyl orcyclopropyl is preferred.

As examples of the “C1-6 haloalkyl” of Group H1 there may be mentionedthe same ones listed above, among which chloromethyl or fluoromethyl isparticularly preferred.

As examples of the “C1-6 alkyl” of Group H1 there may be mentioned thesame ones listed above, among which C1-4 groups are preferred, andmethyl is particularly preferred.

As examples of the “C2-7 alkoxyalkyl” of Group H1 there may be mentionedthe same ones listed above, among which methoxymethyl is preferred.

As examples of the “mono(C1-6 alkyl)aminocarbonyl” of Group H1 there maybe mentioned the same ones listed above, among which methylaminocarbonylis preferred.

As examples of the “di(C1-6 alkyl)aminocarbonyl” of Group H1 there maybe mentioned the same ones listed above, among whichdimethylaminocarbonyl or diethylaminocarbonyl is preferred, anddimethylaminocarbonyl is particularly preferred.

As examples of the “C2-7 alkoxycarbonyl” of Group H1 there may bementioned the same ones listed above, among which methoxycarbonyl orethoxycarbonyl is preferred.

The “C2-7 cyanoalkyl” of H1 is an aforementioned “C1-6 alkyl” havingcyano group bonded thereto, as examples there may be mentionedstraight-chain or branched-chain alkyl groups such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, pentyl,isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl,4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl,3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl,1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1-ethylbutyl or2-ethylbutyl having cyano group bonded thereto, among which C1-4 alkylhaving cyano group bonded thereto is preferred, and cyanomethyl isparticularly preferred.

The term “optionally substituted with a substituent” as used herein hasthe same meaning as “optionally substituted with 1-6 substituents of 1or 2 or more kinds at any desired combination at substitutablepositions”, so long as the number and kind of substituents is notparticularly restricted.

Several of the structural formulas for the compounds throughout thepresent specification represent only one isomeric form for convenience,but the invention encompasses any and all of the geometric isomers aswell as optical isomers based on asymmetric carbons, stereoisomers andtautomers, and mixtures of those isomers, which are implied by thestructures of the compounds, without being limited to any of theformulas shown for convenience. The compounds of the invention thereforeinclude all those having asymmetric carbons therein and existing inoptically active or racemic form, with no particular restrictions on theinvention. There are also no restrictions when polymorphic crystallineforms thereof exist, and the compounds may be in one crystalline form ora mixture of different crystalline forms, while anhydrides and hydratesof the compounds of the invention are also included. Also encompassedwithin the scope of the invention are metabolites of the compounds (1)and (100) of the invention, produced by decomposition of the compoundsin vivo. In addition, the invention further encompasses compounds whichare metabolized in vivo by oxidation, reduction, hydrolysis, conjugationor the like to produce the compounds (1) and (100) of the invention(i.e., “prodrugs”).

The term “salt” as used herein is not particularly restricted so long asa salt is formed with a compound of the invention, and the salt ispharmacologically acceptable, and as examples there may be mentionedinorganic acid salts, organic acid salts, inorganic base salts, organicbase salts, and acidic or basic amino acid salts.

As preferred examples of inorganic acid salts there may be mentionedhydrochloride, hydrobromide, sulfate, nitrate and phosphate, and aspreferred examples of organic acid salts there may be mentioned acetate,succinate, fumarate, maleate, tartarate, citrate, lactate, stearate,benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate andp-toluenesulfonate.

As preferred examples of inorganic base salts there may be mentionedalkali metal salts such as sodium salts and potassium salts, alkalineearth metal salts such as calcium salts and magnesium salts, andaluminum or ammonium salts, and as preferred examples of organic basesalts there may be mentioned diethylamine salts, diethanolamine salts,meglumine salts and N,N′-dibenzylethylenediamine salts.

As preferred examples of acidic amino acid salts there may be mentionedaspartate and glutamate, and as preferred examples of basic amino acidsalts there may be mentioned arginine salts, lysine salts and ornithinesalts.

Preferred compounds according to the invention include the followingcompounds.

(2) the compound, the salt thereof or the hydrate of the foregoing,wherein R10 represents 5- to 10-membered cycloalkyl optionallysubstituted with a substituent selected from Group A2, or 5- to10-membered cycloalkenyl optionally substituted with a substituentselected from Group A2,

wherein Group A2 consists of hydroxyl, phenyl, C1-6 alkyl, C1-6haloalkyl and C2-7 alkylene, where C2-7 alkylene is permissible only inthe case that a spiro union is formed together with the substituted 5-to 10-membered cycloalkyl or the substituted 5- to 10-memberedcycloalkenyl.

(3) the compound, the salt thereof or the hydrate of the foregoing,wherein R10 represents 5- to 10-membered cycloalkyl optionallysubstituted with hydroxyl, phenyl, C1-6 alkyl, C1-6 haloalkyl,1,2-ethylene, trimethylene, tetramethylene or pentamethylene, or 5- to10-membered cycloalkenyl optionally substituted with hydroxyl, phenyl,C1-6 alkyl, C1-6 haloalkyl, 1,2-ethylene, trimethylene, tetramethyleneor pentamethylene, where 1,2-ethylene, trimethylene, tetramethylene orpentamethylene is permissible only in the case that a spiro union isformed together with the substituted 5- to 10-membered cycloalkyl or thesubstituted 5- to 10-membered cycloalkenyl.

(4) the compound, the salt thereof or the hydrate of the foregoing,wherein R10 represents cyclohexyl, 4-t-butylcyclohexyl,4,4-dimethylcyclohexyl, 4,4-dimethylcyclohexyl,3,3,5,5-tetramethylcyclohexyl, 3,5-dimethylcyclohexyl,4-phenylcyclohexyl, 4-trifluoromethylcyclohexyl, 4-n-butylcyclohexyl,cyclopentyl, 3,3,4,4-tetramethylcyclopentyl, cycloheptyl, cyclooctyl ora group represented by the formula:

wherein s represents an integer of 0, 1, 2 or 3.

(4-1) the compound, the salt thereof or the hydrate of the foregoing,wherein R10 represents cyclohexyl.

(4-2) the compound, the salt thereof or the hydrate of the foregoing,wherein R10 represents 4-t-butylcyclohexyl.

(4-3) the compound, the salt thereof or the hydrate of the foregoing,wherein R10 represents 4,4-dimethylcyclohexyl.

(4-4) the compound, the salt thereof, or the hydrate of the foregoing,wherein R10 represents 4,4-dimethylcyclohexyl.

(4-5) the compound, the salt thereof, or the hydrate of the foregoing,wherein R10 represents 3,3,5,5-tetramethylcyclohexyl.

(4-6) the compound, the salt thereof, or the hydrate of the foregoing,wherein R10 represents 3,5-dimethylcyclohexyl.

(4-7) the compound, the salt thereof, or the hydrate of the foregoing,wherein R10 represents 4-phenylcyclohexyl.

(4-8) the compound, the salt thereof, or the hydrate of the foregoing,wherein R10 represents 4-trifluoromethylcyclohexyl.

(4-9) the compound, the salt thereof, or the hydrate of the foregoing,wherein R10 represents 4-n-butylcyclohexyl.

(4-10) the compound, the salt thereof, or the hydrate of the foregoing,wherein R10 represents cyclopentyl.

(4-11) the compound, the salt thereof, or the hydrate of the foregoing,wherein R10 represents 3,3,4,4-tetramethylcyclopentyl.

(4-12) the compound, the salt thereof, or the hydrate of the foregoing,wherein R10 represents cycloheptyl.

(4-13) the compound, the salt thereof, or the hydrate of the foregoing,wherein R10 represents cyclooctyl.

(4-14) the compound, the salt thereof, or the hydrate of the foregoing,wherein R10 represents a group represented by the following formula:

wherein s represents an integer of 0, 1, 2 or 3;

(4-15) the compound, the salt thereof or the hydrate of the foregoing,wherein R10 represents a group represented by the following formula:

(4-16) the compound, the salt thereof or the hydrate of the foregoing,wherein R10 represents a group represented by the following formula:

(4-17) the compound, the salt thereof or the hydrate of the foregoing,wherein R10 represents a group represented by the following formula:

(4-18) the compound, the salt thereof or the hydrate of the foregoing,wherein R10 represents a group represented by the following formula:

(4-19) the compound, the salt thereof or the hydrate of the foregoing,wherein R10 represents a group represented by the following formula:

(4-20) the compound, the salt thereof or the hydrate of the foregoing,wherein R10 represents a group represented by the following formula:

(4-21) the compound, the salt thereof or the hydrate of the foregoing,wherein R10 represents a group represented by the following formula:

wherein s represents an integer of 0, 1, 2 or 3.

(4-22) the compound, the salt thereof or the hydrate of the foregoing,wherein R10 represents a group represented by the following formula:

(4-23) the compound, the salt thereof or the hydrate of the foregoing,wherein R10 represents a group represented by the following formula:

(4-24) the compound, the salt thereof or the hydrate of the foregoing,wherein R10 represents a group represented by the following formula:

(4-25) the compound, the salt thereof or the hydrate of the foregoing,wherein R10 represents a group represented by the following formula:

(4-26) the compound, the salt thereof or the hydrate of the foregoing,wherein R10 represents a group represented by the following formula:

(5) the compound, the salt thereof or the hydrate of the foregoing,wherein R20, R21, R22 and R23 may be the same or different, and eachrepresents hydrogen, hydroxyl, halogen, cyano, C2-7 alkylcarbonyl,nitro, amino, mono(C1-6 alkyl)amino, di(C1-6 alkyl)amino, C1-6 alkyloptionally substituted with a substituent selected from Group B1, C1-6alkoxy optionally substituted with a substituent selected from Group B1,a 4- to 8-membered heterocyclic group optionally substituted with asubstituent selected from Group C1 or a 5- to 6-membered heteroaryl ringgroup optionally substituted with a substituent selected from Group C1.

(6) the compound, the salt thereof or the hydrate of the foregoing,wherein R20, R21, R22 and R23 may be the same or different, and eachrepresents hydrogen, hydroxyl, halogen, cyano, acetyl, nitro, amino,monomethylamine, monoethylamine, dimethylamino, C1-6 alkyl optionallysubstituted with a substituent selected from Group B1, C1-6 alkoxyoptionally substituted with a substituent selected from Group B1, a 4-to 8-membered heterocyclic group optionally substituted with asubstituent selected from Group C1, where the 4- to 8-memberedheterocyclic group is derived by eliminating hydrogen linked to nitrogenof a 4- to 8-membered heterocycle, or a 5- to 6-membered heteroaryl ringgroup optionally substituted with a substituent selected from Group C2,

wherein Group C2 consists of C1-6 alkoxy and C1-6 alkyl.

(7) the compound, the salt thereof or the hydrate of the foregoing,wherein R20, R21, R22 and R23 may be the same or different and eachrepresents hydrogen, halogen, cyano, acetyl, monomethylamine,monoethylamine, dimethylamino, methyl, methoxy, ethoxy, morpholin-4-yloptionally substituted with a substituent selected from Group C2,piperidin-1-yl optionally substituted with a substituent selected fromGroup C2, pyrrolidin-1-yl optionally substituted with a substituentselected from Group C2, azetidin-1-yl, pyridin-2-yl or pyridin-3-yl.

(8) the compound, the salt thereof or the hydrate of the foregoing,wherein at least two of R20, R21, R22 and R23 are hydrogen, and theremaining groups, which may be the same or different, are hydrogen,halogen, cyano, acetyl, monomethylamine, monoethylamine, dimethylamino,methyl, methoxy, ethoxy, morpholin-4-yl optionally substituted with asubstituent selected from Group C2, piperidin-1-yl optionallysubstituted with a substituent selected from Group C2, pyrrolidin-1-yloptionally substituted with a substituent selected from Group C2,azetidin-1-yl, pyridin-2-yl or pyridin-3-yl.

(9) the compound, the salt thereof or the hydrate of the foregoing,wherein three of R20, R21, R22 and R23 are hydrogen, and the remaininggroup is hydrogen, fluorine, cyano, dimethylamino, methyl, methoxy,morpholin-4-yl optionally substituted with a substituent selected fromGroup C3, piperidin-1-yl optionally substituted with a substituentselected from Group C3 or pyrrolidin-1-yl optionally substituted with asubstituent selected from Group C3, wherein Group C3 consists ofmethoxy, ethoxy and methyl.

(9-1) the compound, the salt thereof or the hydrate of the foregoing,wherein at least three of R20, R21, R22 and R23 represent hydrogen, andthe remaining group represents fluorine.

(9-2) the compound, the salt thereof or the hydrate of the foregoing,wherein at least three of R20, R21, R22 and R23 represent hydrogen, andthe remaining group represents cyano.

(9-3) the compound, the salt thereof or the hydrate of the foregoing,wherein at least three of R20, R21, R22 and R23 represent hydrogen, andthe remaining group represents dimethylamino.

(9-4) the compound, the salt thereof or the hydrate of the foregoing,wherein at least three of R20, R21, R22 and R23 represent hydrogen, andthe remaining group represents methyl.

(9-5) the compound, the salt thereof or the hydrate of the foregoing,wherein at least three of R20, R21, R22 and R23 represent hydrogen, andthe remaining group represents methoxy.

(9-6) the compound, the salt thereof or the hydrate of the foregoing,wherein at least three of R20, R21, R22 and R23 represent hydrogen, andthe remaining group represents morpholin-4-yl optionally substitutedwith a substituent selected from Group C2.

(9-7) the compound, the salt thereof or the hydrate of the foregoing,wherein at least three of R20, R21, R22 and R23 represent hydrogen, andthe remaining group represents piperidin-1-yl optionally substitutedwith a substituent selected from Group C2.

(9-8) the compound, the salt thereof or the hydrate of the foregoing,wherein at least three of R20, R21, R22 and R23 represent hydrogen, andthe remaining group represents pyrrolidin-1-yl optionally substitutedwith a substituent selected from Group C2.

(9-9) the compound, the salt thereof or the hydrate of the foregoing,wherein all of R20, R21, R22 and R23 represent hydrogen.

(10) the compound, the salt thereof or the hydrate of the foregoing,wherein R30, R31 and R32 may be the same or different, and eachrepresents hydrogen or C1-6 alkyl, or R30 and R31 bond together to formoxo (═O) and R32 represents hydrogen or C1-6 alkyl.

(11) the compound, the salt thereof or the hydrate of the foregoing,wherein R30, R31 and R32 may be the same or different, and eachrepresents hydrogen or methyl, or R30 and R31 bond together to form oxo(═O) and R32 represents hydrogen or methyl.

(12) the compound, the salt thereof or the hydrate of the foregoing,wherein all of R30, R31 and R32 represent hydrogen.

(13) the compound, the salt thereof or the hydrate of the foregoing,wherein R40 represents C1-6 alkyl optionally substituted with asubstituent selected from Group D1,3- to 8-membered cycloalkyloptionally substituted with a substituent selected from Group E1, C2-7alkenyl, C2-7 alkynyl or C2-7 alkylcarbonyl.

(14) the compound, the salt thereof or the hydrate of the foregoing,wherein R40 represents C1-6 alkyl optionally substituted with asubstituent selected from Group D2,

wherein Group D2 consists of hydroxyl, halogen, cyano, C1-6 alkoxy, 3-to 8-membered cycloalkyl, a 4- to 8-membered heterocyclic group,mono(C1-6 alkyl)aminocarbonyl, di(C1-6 alkyl)aminocarbonyl, C2-7alkylcarbonyl, a 5-membered heteroaryl ring group, 4- to 8-memberedheterocyclic carbonyl or phenyl.

(15) the compound, the salt thereof or the hydrate of the foregoing,wherein R40 represents n-propyl, n-butyl, n-pentyl, isobutyl,ethylcarbonylmethyl, methoxyethyl, ethoxyethyl, cyclopropylmethyl ortetrahydropyran-4-ylmethyl.

(15-1) the compound, the salt thereof or the hydrate of the foregoing,wherein R40 represents n-propyl.

(15-2) the compound, the salt thereof or the hydrate of the foregoing,wherein R40 represents n-butyl.

(15-3) the compound, the salt thereof or the hydrate of the foregoing,wherein R40 represents n-pentyl.

(15-4) the compound, the salt thereof or the hydrate of the foregoing,wherein R40 represents isobutyl.

(15-5) the compound, the salt thereof or the hydrate of the foregoing,wherein R40 represents ethylcarbonylmethyl.

(15-6) the compound, the salt thereof or the hydrate of the foregoing,wherein R40 represents methoxyethyl.

(15-7) the compound, the salt thereof or the hydrate of the foregoing,wherein R40 represents ethoxyethyl.

(15-8) the compound, the salt thereof or the hydrate of the foregoing,wherein R40 represents cyclopropylmethyl.

(15-9) the compound, the salt thereof or the hydrate of the foregoing,wherein R40 represents tetrahydropyran-4-ylmethyl;

(16) the compound, the salt thereof or the hydrate of the foregoing,wherein n represents an integer of 1.

(17) the compound, the salt thereof or the hydrate of the foregoing,wherein X1 represents nitrogen (only in the case of the compoundrepresented by the formula (1)).

Also preferable is a compound, a salt thereof or a hydrate of theforegoing, which are obtained by any combination of:

R10 selected from (2) to (4) and (4-1) to (4-26) above,

R20, R21, R22 and R23 selected from (5) to (9) and (9-1) to (9-9) above,

R30, R31 and R32 selected from (10) to (12) above,

R40 selected from (14) to (15) and (15-1) to (15-9) above,

n selected from (16) above, and

X1 selected from (17) above.

As preferred compounds of the invention there may be mentioned

-   1-[2-(4,4-dimethylcyclohexyl)-5-methoxyphenyl]-4-pentylpiperazine,-   1-butyl-4-[2-(4-t-butylcyclohex-1-enyl)-4-(4-methoxypiperidin-1-yl)phenyl]piperazine,-   1-butyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine,-   1-cyclopropylmethyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine,-   2-{4-[2-(4-t-butylcyclohexyl)phenyl]piperazin-1-yl}-N-ethylacetamide,-   cis-4-(4-t-butylcyclohexyl)-3-(4-butylpiperazine-1-yl)benzonitrile,-   trans-4-(4-t-butylcyclohexyl)-3-(4-butylpiperazine-1-yl)benzonitrile,-   1-butyl-4-(2-cyclohexylphenyl)piperazine,-   1-butyl-4-[2-(4-t-butylcyclohexyl)phenyl]piperazine,-   1-{4-[2-(4,4-dimethylcyclohexyl)phenyl]piperazin-1-yl}butan-2-one,-   4-[3-(4-t-butylcyclohex-1-enyl)-4-(4-butylpiperazine-1-yl)phenyl]morpholine,-   1-[2-(4-t-butylcyclohexyl)phenyl]-4-(2-methoxyethyl)piperazine,-   1-[2-(4-t-butylcyclohex-1-enyl)-4-(4-methoxypiperidin-1-yl)phenyl]-4-cyclopropylmethylpiperazine,-   1-(tetrahydropyran-4-ylmethyl)-4-[2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazine,-   4-[4-(4-propylpiperazin-1-yl)-3-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]morpholine,-   1-{4-[2-(4,4-diethylcyclohex-1-enyl)-4-morpholin-4-ylphenyl]piperazin-1-yl}butan-2-one,-   1-propyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine,-   1-butyl-4-[4-(4-methoxypiperidin-1-yl)-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine,-   1-butyl-4-[2-(3,5-dimethylcyclohexyl)phenyl]piperazine,-   1-[2-(4,4-dimethylcyclohexyl)phenyl]-4-(tetrahydropyran-4-ylmethyl)piperazine,-   4-[4-(4-butylpiperazine-1-yl)-3-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]morpholine,-   4-[4-(4-butylpiperazine-1-yl)-3-(3,3,5,5-tetramethylcyclohexyl)phenyl]morpholine,-   1-[4-(4-ethoxypiperidin-1-yl)-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-propylpiperazine,-   cis-4-[4-(4-butylpiperazine-1-yl)-3-(4,4-dimethylcyclohexyl)phenyl]-2,6-dimethylmorpholine,-   4-{4-(4-pentylpiperazin-1-yl)-3-spiro[2.5]oct-6-ylphenyl}morpholine,-   1-[3-fluoro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]-4-propylpiperazine,-   1-cyclopropylmethyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-1,2,3,6-tetrahydropyridine,-   1-butyl-4-{2-(3,3,4,4-tetramethylcyclopentyl)phenyl}piperazine,-   1-butyl-4-[2-(4,4-dimethylcyclohexyl)-4-(4-ethoxypiperidin-1-yl)phenyl]piperazine,-   1-butyl-4-[2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazine,-   1-cyclopropylmethyl-4-[2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazine,-   1-{4-[2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazin-1-yl}butan-2-one,-   1-(2-methoxyethyl)-4-[2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazine,-   1-{4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazin-1-yl}butan-2-one,-   1-(2-methoxyethyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine,-   4-[4-(4-butylpiperazine-1-yl)-5-(4,4-dimethylcyclohexyl)-2-methoxyphenyl]-morpholine,-   1-butyl-4-(2-spiro[4.5]dec-8-ylphenyl)piperazine,-   1-[2-(4,4-dimethylcyclohex-1-enyl)phenyl]-4-isobutylpiperazine,-   1-cyclopropylmethyl-4-[2-(4,4-dimethylcyclohexyl)-4-(4-methoxypiperidin-1-yl)phenyl]piperazine,-   4-[3-(4,4-dimethylcyclohexyl)-4-(4-isobutylpiperazine-1-yl)phenyl]morpholine,-   {4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazin-1-yl}acetonitrile,-   1-(2-ethoxyethyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine,-   (R)-1-butyl-4-[2-(4,4-dimethylcyclohexyl)-4-(3-methoxypyrrolidin-1-yl)phenyl]piperazine,-   1-[4-methyl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-propylpiperazine,-   1-[4-methoxy-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-(tetrahydropyran-4-ylmethyl)piperazine,-   1-butyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperidine,-   1-isobutyl-4-[2-(3,3,4,4-tetramethylcyclopent-1-enyl)phenyl]piperazine,    and-   1-[2-(4-cyclopropylmethylpiperazin-1-yl)phenyl]-3,3,5,5-tetramethylcyclohexanol.

In addition to the compounds above, the following compounds are alsopreferable compounds. The definitions of the terms in the followingcompounds are similar to those defined above.

-   <101> A compound represented by the following general formula, a    salt thereof or a hydrate of the foregoing.

wherein R10 represents cyclohexyl optionally substituted with asubstituent selected from Group A1′ or cyclohexenyl optionallysubstituted with a substituent selected from Group A1′,

R20, R21, R22 and R23 may be the same or different and each representshydrogen, hydroxyl, halogen, cyano, nitro, amino, mono(C1-6 alkyl)amino,di(C1-6 alkyl)amino, C1-6 alkyl optionally substituted with asubstituent selected from Group B1′, C1-6 alkoxy optionally substitutedwith a substituent selected from Group B1′, a 4- to 8-memberedheterocyclic group optionally substituted with a substituent selectedfrom Group C1′ or a 5- to 10-membered heteroaryl ring group optionallysubstituted with a substituent selected from Group C1′,

R30, R31 and R32 may be the same or different and each representshydrogen, hydroxyl, halogen, cyano, carboxyl, C1-6 alkyl, C1-6 alkoxy orC2-7 alkoxycarbonyl, or

two of R30, R31 and R32 bond together to form oxo (═O),

R40 represents C1-10 alkyl optionally substituted with a substituentselected from Group D1′ or 3- to 8-membered cycloalkyl,

n represents an integer of 1 or 2, and

X1 represents CH or nitrogen,

wherein Group A1′ consists of halogen, C1-6 alkyl and C2-7 alkylene,where C2-7 alkylene is permissible only in the case that a spiro unionis formed together with cyclohexyl or cyclohexenyl,

Group B1′ consists of halogen,

Group C1′ consists of cyano, halogen, C1-6 alkyl and C1-6 alkoxy, and

Group D1′ consists of hydroxyl, halogen, cyano, C1-6 alkoxy, 3- to8-membered cycloalkyl, a 4- to 8-membered heterocyclic group, a 5- to10-membered heteroaryl ring group, C2-7 alkylcarbonyl, mono(C1-6alkyl)aminocarbonyl, di(C1-6 alkyl)aminocarbonyl, 4- to 8-memberedheterocyclic carbonyl and 5- to 10-membered heteroaryl ring carbonyl.

-   <102> The compound according to <101>, the salt thereof or the    hydrate of the foregoing, wherein R10 represents cyclohexyl    optionally substituted with a substituent selected from Group A2′,    or cyclohexenyl optionally substituted with a substituent selected    from Group A2′, wherein Group A2′ consists of C1-6 alkyl and C2-7    alkylene, where C2-7 alkylene is permissible only in the case that a    spiro union is formed together with cyclohexyl or cyclohexenyl.-   <103> The compound according to <101>, the salt thereof or the    hydrate of the foregoing, wherein R10 represents cyclohexyl    optionally substituted with C1-6 alkyl, 1,2-ethylene, trimethylene,    tetramethylene or pentamethylene, or cyclohexenyl optionally    substituted with C1-6 alkyl, 1,2-ethylene, trimethylene,    tetramethylene or pentamethylene,

where 1,2-ethylene, trimethylene, tetramethylene or pentamethylene ispermissible only in the case that a spiro union is formed together withcyclohexyl or cyclohexenyl.

-   <104> The compound according to <101>, the salt thereof or the    hydrate of the foregoing, wherein R10 represents cyclohexyl,    4-(t-butyl)cyclohexyl, 4,4-dimethylcyclohexyl,    4,4-dimethylcyclohexyl, 3,3,5,5-tetramethylcyclohexyl, or a group    represented by the formula:

wherein s represents an integer of 0-3.

-   <105> The compound according to any one of <101> to <104>, the salt    thereof or the hydrate of the foregoing, wherein R20, R21, R22 and    R23 may be the same or different, and each represents hydrogen,    halogen, cyano, amino, mono(C1-6 alkyl)amino, di(C1-6 alkyl)amino,    C1-6 alkyl optionally substituted with fluorine, C1-6 alkoxy    optionally substituted with fluorine, or a 4- to 8-membered    heterocyclic group optionally substituted with a substituent    selected from Group C2′, wherein Group C2′ consists of C1-6 alkoxy    and C1-6 alkyl.-   <106> The compound according to any one of <101> to <104>, the salt    thereof or the hydrate of the foregoing, wherein R20, R21, R22 and    R23 may be the same or different, and each represents hydrogen,    halogen, cyano, amino, monomethylamino, dimethylamino, methyl,    methoxy, morpholino optionally substituted with a substituent    selected from Group C2′ or piperidino optionally substituted with a    substituent selected from Group C2′, wherein Group C2′ consists of    C1-6 alkoxy and C1-6 alkyl.-   <107> The compound according to any one of <101> to <104>, the salt    thereof or the hydrate of the foregoing, wherein at least three of    R20, R21, R22 and R23 are hydrogen, and the remaining group is    hydrogen, halogen, methoxy or cyano.-   <108> The compound according to any one of <101> to <107>, the salt    thereof or the hydrate of the foregoing, wherein R30, R31 and R32    may be the same or different, and each represents hydrogen or C1-6    alkyl, or R30 and R31 bond together to form oxo (═O) and R32    represents hydrogen or C1-6 alkyl.-   <109> The compound according to any one of <101> to <107>, the salt    thereof or the hydrate of the foregoing, wherein R30, R31 and R32    may be the same or different, and each represents hydrogen or    methyl, or R30 and R31 bond together to form oxo (═O) and R32    represents hydrogen or methyl.-   <110> The compound according to any one of <101> to <107>, the salt    thereof or the hydrate of the foregoing, wherein all of R30, R31 and    R32 represent hydrogen.-   <111> The compound according to any one of <101> to <110>, the salt    thereof or the hydrate of the foregoing, wherein R40 represents C1-6    alkyl optionally substituted with a substituent selected from Group    D2′, wherein Group D2′ consists of C1-6 alkoxy, 3- to 8-membered    cycloalkyl, a 4- to 8-membered heterocyclic group, cyano, mono(C1-6    alkyl)aminocarbonyl, C2-7 alkylcarbonyl and 4- to 8-membered    heterocyclic carbonyl.-   <112> The compound according to any one of <101> to <110>, the salt    thereof or the hydrate of the foregoing, wherein R40 represents C1-6    alkyl optionally substituted with a substituent selected from Group    D3′, wherein Group D3′ consists of methoxy, ethoxy, cyclopropyl,    cyano, ethylaminocarbonyl, n-propylaminocarbonyl, ethylcarbonyl,    piperidinocarbonyl and 4-tetrahydropyranyl.-   <113> The compound according to any one of <101> to <110>, the salt    thereof or the hydrate of the foregoing, wherein R40 represents    n-propyl, n-butyl, n-pentyl, ethylcarbonylmethyl, methoxyethyl,    ethoxyethyl, cyclopropylmethyl or 4-tetrahydropyranylmethyl.-   <114> The compound according to any one of <101> to <113>, the salt    thereof or the hydrate of the foregoing, wherein n represents an    integer of 1.-   <115> The compound according to any one of <101> to <114>, the salt    thereof or the hydrate of the foregoing, wherein X1 represents    nitrogen.-   <117> A medicament comprising the compound according to <101>, the    salt thereof or the hydrate of the foregoing.-   <118> A cell adhesion inhibitor or cell infiltration inhibitor    comprising the compound according to <101>, the salt thereof or the    hydrate of the foregoing.-   <119> A therapeutic or prophylactic agent for inflammatory bowel    disease, rheumatoid arthritis, psoriasis, multiple sclerosis, asthma    or atopic dermatitis, comprising the compound according to <101>,    the salt thereof or the hydrate of the foregoing.-   <120> A therapeutic or prophylactic agent for an inflammatory bowel    disease, comprising the compound according to <101>, the salt    thereof or the hydrate of the foregoing.-   <121> A therapeutic or prophylactic agent for ulcerative colitis or    Crohn's disease, comprising the compound according to <101>, the    salt thereof or the hydrate of the foregoing.

The compounds of the invention have excellent cell adhesion inhibitoryaction or cell infiltration inhibitory action, and are therefore usefulas therapeutic or prophylactic agents for inflammatory diseases andautoimmune diseases, particularly as therapeutic or prophylactic agentsfor various diseases associated with adhesion and infiltration ofleukocytes, such as inflammatory bowel disease (particularly ulcerativecolitis or Crohn's disease), irritable bowel syndrome, rheumatoidarthritis, psoriasis, multiple sclerosis, asthma and atopic dermatitis.

BEST MODE FOR CARRYING OUT THE INVENTION

The compounds (1) and (100) of the invention may be produced by themethods described below. However, it is to be understood that theproduction methods for the compounds of the invention are not limited tothose described below.

Compound (1) according to the invention may be produced by the followingMethod A, Method B, Method C, Method D, Method E, Method N, Method P orMethod V.

Compound (1A), the compound (1) according to the invention wherein X1 isnitrogen may be produced by the following Method F, Method G Method H,Method K, Method M, Method Q or Method R.

Compound (1B), the compound (1) according to the invention wherein X1 isa group of the formula CH, and Compound (100) of the invention may beproduced by the following Method A, Method B, Method C, Method D, MethodE, Method K, Method M, Method S, Method T or Method U.

Each of these methods will now be explained in detail.

Method A is a method of producing compound (1) of the invention byreacting compound (2) with an alkylating agent (3), carbonylating agent(3) or sulfonylating agent (3) in an inert solvent, in the presence orin the absence of a base, in the presence or in the absence of anadditive, and optionally removing any protecting groups on the resultantcompound, or a method of producing compound (100) of the invention byreacting compound (200) in a similar manner.

In this scheme, R10, R20, R21, R22, R23, R30, R31, R32, R40, X1 and nhave the same definitions as above, R10a, R20a, R21a, R22a, R23a, R30a,R31a, R32a and R40a have the same definitions as the correspondinggroups R10, R20, R21, R22, R23, R30, R31, R32 and R40, or are thecorresponding groups R10, R20, R21, R22, R23, R30, R31, R32 and R40 withthe respective substituents on the groups protected, and W1 represents aleaving group which is chlorine, bromine or iodine, alkylsulfonyloxysuch as methanesulfonyloxy or ethanesulfonyloxy, haloalkanesulfonyloxysuch as trifluoromethanesulfonyloxy or nonafluorobutanesulfonyloxy, orarylsulfonyloxy such as benzenesulfonyloxy or p-toluenesulfonyloxy,among which chlorine, bromine, iodine, methanesulfonyloxy,p-toluenesulfonyloxy, nonafluorobutanesulfonyloxy ortrifluoromethanesulfonyloxy is preferred.

(Alkylation)

There are no particular restrictions on the solvent used so long as itdissolves the starting compound to some extent and does not inhibit thereaction of this step, and specifically there may be mentioned amidessuch as formamide, dimethylformamide, dimethylacetamide,hexamethylphosphoric triamide and N-methylpyrrolidone, nitriles such asacetonitrile and isobutyronitrile, aromatic hydrocarbons such astoluene, benzene and xylene, ethers such as diethyl ether, diisopropylether, tetrahydrofuran, dioxane, dimethoxyethane and diethyleneglycoldimethyl ether or sulfoxides such as dimethyl sulfoxide, as well asmixtures of these solvents, among which dimethylformamide, acetonitrile,toluene or tetrahydrofuran is preferred.

There are no particular restrictions on the base used so long as it canyield the target compound and does not produce any unseparableby-products, and specifically there may be mentioned organic bases suchas triethylamine and pyridine or inorganic bases such as potassiumcarbonate, sodium carbonate, potassium hydrogencarbonate, sodiumhydrogencarbonate and cesium carbonate, among which potassium carbonateor triethylamine is preferred.

Sodium iodide or potassium iodide is used as an additive to acceleratethe reaction if necessary.

The reaction temperature will differ depending on the startingmaterials, solvent and reagents, but will usually be between −30° C. and180° C., and is preferably between 0° C. and 120° C.

The reaction time will differ depending on the starting materials,solvent, reagents and reaction temperature, but will usually be 0.5 to100 hours, and is preferably 0.5 to 24 hours.

(Carbonylation or Sulfonylation)

There are no particular restrictions on the solvent used so long as itdissolves the starting compound to some extent and does not inhibit thereaction of this step, and specifically there may be mentionedhalogenated hydrocarbons such as chloroform, dichloromethane,1,2-dichloroethane and carbon tetrachloride, ethers such as diethylether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane anddiethyleneglycol dimethyl ether, amides such as formamide,dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide andN-methylpyrrolidone, organic bases such as pyridine, or water, as wellas mixtures of these solvents, among which dichloromethane,tetrahydrofuran, dioxane, dimethylformamide, pyridine or water, ormixtures thereof, are preferred.

There are no particular restrictions on the base used so long as it canyield the target compound and does not produce any unseparableby-products, and specifically there may be mentioned organic bases suchas triethylamine and pyridine or inorganic bases such as potassiumcarbonate, sodium carbonate, potassium hydrogencarbonate, sodiumhydrogencarbonate, cesium carbonate and sodium hydroxide, among whichpotassium carbonate or triethylamine is preferred.

4-Dimethylaminopyridine is used as an additive to accelerate thereaction if necessary.

The reaction temperature will differ depending on the startingmaterials, solvent and reagents, but will usually be between −70° C. and120° C., and is preferably between −70° C. and 60° C.

The reaction time will differ depending on the starting materials,solvent, reagents and reaction temperature, but will usually be 0.5 to48 hours, and is preferably 0.5 to 12 hours.

Compounds (1) and (100) of the invention may be isolated or purifiedfrom the reaction mixture obtained above, by the method described below.

When R10 of the resultant compounds (1) and (100) is optionallysubstituted 5- to 10-membered cycloalkenyl, it may be subjected tohydrogenation to yield compounds (1) or (1B) (the compound (1) whereinX1 is CH) of the invention wherein R10 is 5- to 10-membered cycloalkyloptionally substituted with the corresponding substituent.

When R10 of the resultant compound (100) is optionally substituted 5- to10-membered cycloalkyl, it may be subjected to hydrogenation to yieldcompound (1B) (the compound (1) wherein X1 is CH) of the invention.

The hydrogenation may be carried out as follows.

Specifically, hydrogenation reaction may be carried out using a metalcatalyst in an inert solvent, under a hydrogen atmosphere or in thepresence of hydrogen-donating reagent, in the presence or in the absenceof an acid.

There are no particular restrictions on the solvent used so long as itdissolves the starting compound to some extent and does not inhibit thereaction of this step, and specifically there may be mentioned water,alcohols such as methanol and ethanol, ethers such as diethyl ether,diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane anddiethyleneglycol dimethyl ether, esters such as methyl acetate, ethylacetate, propyl acetate, butyl acetate and diethyl carbonate, amidessuch as formamide, dimethylformamide, dimethylacetamide,hexamethylphosphoric triamide and N-methylpyrrolidone, aliphatichydrocarbons such as hexane, heptane, ligroin and petroleum ether ororganic acids such as acetic acid, or mixtures of these solvents, amongwhich methanol, ethanol, ethyl acetate, tetrahydrofuran, a mixed solventof methanol and tetrahydrofuran, or a mixed solvent of ethanol andtetrahydrofuran is preferred.

There are no particular restrictions on the metal catalyst used so longas it can yield the target compound and does not produce any unseparableby-products, and specifically there may be mentioned heterogeneous raremetal catalysts such as palladium, palladium hydroxide, platinum,platinum oxide, rhodium, ruthenium and nickel (preferably supported on acarrier such as activated carbon, alumina, silica or zeolite) andhomogeneous metal complex catalysts such aschlorotris(triphenylphosphine)rhodium(I) (Wilkinson's complex), amongwhich heterogeneous rare metal catalysts (especially 5 to 10%palladium-activated carbon or platinum oxide, optionally wetted withwater) are preferred.

The number of equivalents of the metal catalyst used (including thecarrier) will differ depending on the starting materials, solvent andreagents, but will usually be a proportion of 0.05 to 10 and preferably0.05 to 3, in terms of the weight ratio with respect to the startingmaterial.

There are no particular restrictions on the acid used so long as it canyield the target compound and does not produce any unseparableby-products, and specifically there may be mentioned organic acids suchas methanesulfonic acid, trifluoromethanesulfonic acid, acetic acid andtrifluoroacetic acid, or inorganic acids such as hydrochloric acid andhydrobromic acid.

The reaction temperature will differ depending on the startingmaterials, solvent and reagents, but will usually be between −10° C. and80° C., and is preferably between 0° C. and 50° C.

The reaction pressure of the hydrogen will also differ depending on thestarting materials, solvent and reagents, but will usually be between 1and 100 atmospheres, and preferably between 1 and 5 atmospheres.

The reaction time will differ depending on the starting materials,solvent, reagents and reaction temperature, but will usually be 0.5 to200 hours, and is preferably 0.5 to 100 hours.

When the resultant compound is to be converted to an acid salt, this maybe accomplished by a conventional method. The step of producing the saltand the step of hydrogenation may be carried out in a different orderwhere appropriate.

Method B is a method of producing compound (1) of the invention byreacting compound (2) with an acid anhydride (4) in an inert solvent, inthe presence or in the absence of a base, and optionally removing anyprotecting groups on the resultant compound, or a method of producingcompound (100) of the invention by reacting compound (200) in a similarmanner.

In this scheme, R10, R20, R21, R22, R23, R30, R31, R32, R40, X1, n,R10a, R20a, R21a, R22a, R23a, R30a, R31a and R32a have the samedefinitions as above. Also, R40b is a group comprising carbonyl orsulfonyl, which is suitable for obtaining R40 and can form an acidanhydride. Substituents on R40b may also be protected.

This method may also be carried out in a manner similar to thecarbonylation or sulfonylation step of Method A described above.

Compounds (1) and (100) of the invention may be isolated or purifiedfrom the reaction mixture obtained above, by the method described below.

When R10 of the resultant compounds (1) and (100) is optionallysubstituted 5- to 10-membered cycloalkenyl, it may be subjected to thehydrogenation described above in Method A to yield compound (1) of theinvention or compound (1B) of the invention (the compound (1) wherein X1is CH) wherein R10 is 5- to 10-membered cycloalkyl optionallysubstituted with the corresponding substituent.

When R10 of the resultant compound (100) is optionally substituted 5- to10-membered cycloalkyl, it may be subjected to hydrogenation to yieldcompound (1B) (the compound (1) wherein X1 is CH) of the invention.

When the resultant compound is to be converted to an acid salt, this maybe carried out by a conventional method. The step of producing the saltand the step of hydrogenation may be carried out in a different orderwhere appropriate.

Method C is a method of producing compound (1) of the invention byreacting compound (2) with an aldehyde (5) or ketone (5) in an inertsolvent, in the presence of a reducing agent, in the presence or in theabsence of an acid, in the presence or in the absence of an additive,and optionally removing any protecting groups on the resultant compound,or a method of producing compound (100) of the invention by reactingcompound (200) in a similar manner.

In this scheme, R10, R20, R21, R22, R23, R30, R31, R32, R40, X1, n,R10a, R20a, R21a, R22a, R23a, R30a, R31a and R32a have the samedefinitions as above. Also, A1 and A2 are groups suitable for obtainingR40. Substituents on A1 or A2 may also be protected.

There are no particular restrictions on the solvent used so long as itdissolves the starting compound to some extent and does not inhibit thereaction of this step, and specifically there may be mentioned etherssuch as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,dimethoxyethane and diethyleneglycol dimethyl ether, halogenatedhydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane andcarbon tetrachloride, nitriles such as acetonitrile andisobutyronitrile, aromatic hydrocarbons such as toluene, benzene andchlorobenzene or alcohols such as methanol and ethanol, among whichethers (particularly tetrahydrofuran) and halogenated hydrocarbons(particularly dichloroethane) are preferred.

There are no particular restrictions on the reducing agent used so longas it can yield the target compound and does not produce any unseparableby-products, and specifically there may be mentioned boron reducingagents such as sodium triacetoxyborohydride, sodium cyanoborohydride andborane-pyridine, and metal catalyst-hydrogen gas, among which sodiumtriacetoxyborohydride is preferred.

There are no particular restrictions on the acid used so long as it canyield the target compound and does not produce any unseparableby-products, and specifically there may be mentioned organic acids suchas acetic acid and trifluoroacetic acid or Lewis acids such as titaniumtetraisopropoxide and zinc chloride, among which organic acids(particularly acetic acid) are preferred.

There are no particular restrictions on the use of an additive so longas it can yield the target compound and does not produce any unseparableby-products, and specifically there may be mentioned molecular sieve ormagnesium sulfate, among which Molecular Sieve 4 Å is preferred.

The reaction temperature will differ depending on the startingmaterials, solvent and reagents, but will usually be between −70° C. and120° C., and is preferably between 0° C. and 50° C.

The reaction time will differ depending on the starting materials,solvent, reagents and reaction temperature, but will usually be 0.1 to200 hours, and is preferably 0.1 to 24 hours.

As supplementary literature to be used as reference for carrying outthis method, there may be mentioned, but not limited to, Ahmed F.Abdel-Magid et al., J. Org. Chem. (1996), 61, 3849.

Compounds (1) and (100) of the invention may be isolated or purifiedfrom the reaction mixture obtained above, by the method described below.

When R10 of the resultant compounds (1) and (100) is optionallysubstituted 5- to 10-membered cycloalkenyl, it may be subjected to thehydrogenation described above in Method A to yield compound (1) of theinvention or compound (1B) (the compound (1) wherein X1 is CH) whereinR10 is 5- to 10-membered cycloalkyl optionally substituted with thecorresponding substituent.

When R10 of the resultant compound (100) is optionally substituted 5- to10-membered cycloalkyl, it may be subjected to hydrogenation to yieldcompound (1B) (the compound (1) wherein X1 is CH) of the invention.

When the resultant compound is to be converted to an acid salt, this maybe carried out by a conventional method. The step of producing the saltand the step of hydrogenation may be carried out in a different orderwhere appropriate.

Method D is a method of producing compound (1) of the invention byreacting compound (2) with a conjugated carbonyl compound (6) by Michaeladdition reaction in an inert solvent, and optionally removingprotecting groups on the resultant compound, or a method of producingcompound (100) of the invention by reacting compound (200) in a similarmanner.

In this scheme, R10, R20, R21, R22, R23, R30, R31, R32, R40, X1, n,R10a, R20a, R21a, R22a, R23a, R30a, R31a and R32a have the samedefinitions as above. Also, Z1, Z2, Z3 and Z4 are groups suitable forobtaining R40. Substituents on Z1, Z2, Z3 and Z4 may also be protected.

There are no particular restrictions on the solvent used so long as itdissolves the starting compound to some extent and does not inhibit thereaction of this step, and specifically there may be mentioned alcoholssuch as methanol, ethanol, n-propanol, isopropanol, n-butanol,isobutanol, t-butanol, isoamyl alcohol, diethylene glycol and glycerin,halogenated hydrocarbons such as chloroform, dichloromethane,1,2-dichloroethane and carbon tetrachloride, ethers such as diethylether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane anddiethyleneglycol dimethyl ether, amides such as formamide,dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide andN-methylpyrrolidone, and aromatic hydrocarbons such as benzene, tolueneand xylene, among which halogenated hydrocarbons (particularlychloroform) or ethers (particularly tetrahydrofuran) are preferred.

The reaction temperature will differ depending on the startingmaterials, solvent and reagents, but will usually be between −30° C. and150° C., and is preferably between 0° C. and 120° C.

The reaction time will differ depending on the starting materials,solvent, reagents and reaction temperature, but will usually be 0.5 to48 hours, and is preferably 0.5 to 24 hours.

Compounds (1) and (100) of the invention may be isolated or purifiedfrom the reaction mixture obtained above, by the method described below.

When R10 of the resultant compounds (1) and (100) is optionallysubstituted 5- to 10-membered cycloalkenyl, it may be subjected to thehydrogenation described above in Method A to yield compound (1) of theinvention or compound (1B) of the invention (the compound (1) wherein X1is CH) wherein R10 is 5- to 10-membered cycloalkyl optionallysubstituted with the corresponding substituent.

When R10 of the resultant compound (100) is optionally substituted 5- to10-membered cycloalkyl, it may be subjected to hydrogenation to yieldcompound (1B) (the compound (1) wherein X1 is CH) of the invention.

When the resultant compound is to be converted to an acid salt, this maybe carried out by a conventional method. The step of producing the saltand the step of hydrogenation may be carried out in a different orderwhere appropriate.

Method E is a method of producing compound (1) of the invention byreacting compound (2) with an isocyanate compound (7) or a substitutedaminocarbonylchloride compound (7) in an inert solvent, in the presenceor in the absence of a base, and optionally removing protecting groupson the resultant compound, or a method of producing compound (100) ofthe invention by reacting compound (200) in a similar manner.

In this scheme, R10, R20, R21, R22, R23, R30, R31, R32, R40, X1, n,R10a, R20a, R21a, R22a, R23a, R30a, R31a and R32a have the samedefinitions as above. Also, A3, A4 and A5 are groups suitable forobtaining R40. Substituents on A3, A4 and A5 may also be protected.

There are no particular restrictions on the solvent used so long as itdissolves the starting compound to some extent and does not inhibit thereaction of this step, and specifically there may be mentionedhalogenated hydrocarbons such as chloroform, dichloromethane,1,2-dichloroethane and carbon tetrachloride, aromatic hydrocarbons suchas benzene, toluene and chlorobenzene, and ethers such as diethyl ether,diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane anddiethyleneglycol dimethyl ether, among which dichloromethane ortetrahydrofuran is preferred.

There are no particular restrictions on the base used so long as it canyield the target compound and does not produce any unseparableby-products, and specifically there may be mentioned organic bases suchas N-methylmorpholine, triethylamine, tripropylamine, tributylamine,diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine,4-pyrrolidinopyridine, picoline, 4-(N,N-dimethylamino)pyridine,2,6-di(t-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline,N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN),1,4-diazabicyclo[2.2.2]octane (DABCO) and1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), among which triethylamine orpyridine is preferred.

The reaction temperature will differ depending on the startingmaterials, solvent and reagents, but will usually be between −70° C. and100° C.

The reaction time will differ depending on the starting materials,solvent, reagents and reaction temperature, but will usually be 1 to 24hours.

Compound (1) of the invention may be isolated or purified from thereaction mixture obtained above, by the method described below.

When R10 of the resultant compounds (1) and (100) is optionallysubstituted 5- to 10-membered cycloalkenyl, it may be subjected to thehydrogenation described above in Method A to yield compound (1) of theinvention or compound (1B) of the invention (the compound (1) wherein X1is CH) wherein R10 is 5- to 10-membered cycloalkyl optionallysubstituted with the corresponding substituent.

When R10 of the resultant compound (100) is optionally substituted 5- to10-membered cycloalkyl, it may be subjected to hydrogenation to yieldcompound (1B) (the compound (1) wherein X1 is CH) of the invention.

When the resultant compound is to be converted to an acid salt, this maybe carried out by a conventional method. The step of producing the saltand the step of hydrogenation may be carried out in a different orderwhere appropriate.

Method F is a method of producing compound (1A) of the invention (thecompound according to the formula (1) above wherein X1 is nitrogen) byreacting compound (8) with compound (9) (amination or amidation) in aninert solvent, in the presence of a palladium(0) catalyst or coppercatalyst, in the presence or in the absence of a base, in the presenceor in the absence of an additive, under or not under an inert gasatmosphere, and optionally removing protecting groups on the resultantcompound.

In this scheme, R10, R20, R21, R22, R23, R30, R31, R32, R40, n, R10a,R20a, R21a, R22a, R23a, R30a, R31a and R32a have the same definitions asabove. Also, W1a represents chlorine, bromine or iodine, or atrifluoromethanesulfonyloxy group.

(Reaction in the Presence of Palladium(0) Catalyst)

There are no particular restrictions on the solvent used so long as itdissolves the starting compound to some extent and does not inhibit thereaction of this step, and specifically there may be mentioned amidessuch as dimethylformamide, dimethylacetamide, hexamethylphosphorictriamide and N-methylpyrrolidone, aromatic hydrocarbons such as toluene,benzene, xylene and mesitylene, ethers such as diethyl ether,diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane anddiethyleneglycol dimethyl ether, alcohols such as methanol, ethanol,n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamylalcohol, diethylene glycol, glycerin, octanol and cyclohexanol, nitrilessuch as acetonitrile and isobutyronitrile, or mixtures of thesesolvents, among which dimethylformamide, toluene, xylene,tetrahydrofuran, dioxane or dimethoxyethane is preferred.

There are no particular restrictions on the palladium(0) catalyst usedso long as it can yield the target compound and does not produce anyunseparable by-products, and specifically there may be mentionedtetrakis(triphenylphosphine)palladium,tris(dibenzylideneacetone)dipalladium,bis(dibenzylideneacetone)palladium, bis(tri-t-butylphosphine)palladiumand palladium black, or palladium(0) catalysts produced in the reactionsystem by combination of the palladium complexes which can bepalladium(0) precursors mentioned below and various ligands mentionedbelow.

There are no particular restrictions on various palladium complexeswhich can be used as palladium(0) precursors, so long as they can yieldthe target compound without producing any unseparable by-products, andspecifically there may be mentioned palladium acetate,1,1′-bis(diphenylphosphino)ferrocene dichloropalladium,dichlorobis(tri-o-tolylphosphine)palladium,dichlorobis(triscyclohexylphosphine)palladium, and the like.

There are no particular restrictions on ligands used so long as they canyield the target compound without producing any unseparable by-products,and specifically there may be mentioned2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP),9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (Xantphos),tri-t-butylphosphine, tri(4-methylphenyl)phosphine,tri-2-furylphosphine, 2-(di-t-butylphosphino)biphenyl,2-(dicyclohexylphosphino)biphenyl, tricyclohexylphosphine,2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl,1,1′-bis(diphenylphosphino)ferrocene, di-t-butylphosphoniumtetrafluoroborate and 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene.

There are no particular restrictions on the base used so long as it canyield the target compound and does not produce any unseparableby-products, and specifically there may be mentioned inorganic basessuch as sodium t-butoxide, potassium t-butoxide, tripotassium phosphate,trisodium phosphate, cesium carbonate, potassium carbonate, sodiumcarbonate, cesium bicarbonate, potassium hydrogencarbonate, sodiumhydrogencarbonate, sodium acetate, potassium acetate, cesium acetate,potassium fluoride, cesium fluoride, sodium hydroxide and potassiumhydroxide, or organic bases such as triethylamine,1,8-bis(dimethylamino)naphthalene, 1,4-diazabicyclo[2.2.2]octane (DABCO)and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

There are no particular restrictions on the additive used so long as itcan yield the target compound and does not produce any unseparableby-products, and specifically there may be mentioned lithium fluoride,sodium fluoride, lithium chloride, sodium chloride, lithium bromide,sodium bromide, 1,4,7,10,13,16-hexaoxacyclooctadecane (18-Crown-6),1,4,7,10,13-pentaoxacyclopentadecane (15-Crown-5), tetrabutylammoniumfluoride and tetrabutylammonium bromide.

The reaction temperature will differ depending on the startingmaterials, solvent and reagents, but will usually be between 0° C. and150° C., and is preferably between 20° C. and 110° C.

The reaction time will differ depending on the starting materials,solvent, reagents and reaction temperature, but will usually be 0.1 to100 hours, and is preferably 0.5 to 48 hours.

When the reaction is carried out in an inert gas atmosphere, the inertgas is not particularly restricted so long as it does not inhibit thereaction of this step, and specifically it may be argon or nitrogen gas.

As supplementary literature to be used as reference for carrying outthis method, there may be mentioned, but not limited to, D. Prim et al.,Tetrahedron (2002), 58, 2041 and L. Buchwald et al., J. Organomet. Chem.(1999), 576, 125.

(Reaction in the Presence of Copper Catalyst)

There are no particular restrictions on the solvent used so long as itdissolves the starting compound to some extent and does not inhibit thereaction of this step, and specifically there may be mentioned amidessuch as formamide, dimethylformamide, dimethylacetamide,hexamethylphosphoric triamide and N-methylpyrrolidone, aromatichydrocarbons such as toluene, benzene, xylene, mesitylene andnitrobenzene, ethers such as diethyl ether, diisopropyl ether,tetrahydrofuran, dioxane, dimethoxyethane and diethyleneglycol dimethylether, alcohols such as methanol, ethanol, n-propanol, isopropanol,n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol,glycerin, octanol, cyclohexanol and methylcellosolve, or mixtures ofthese solvents, among which isopropanol, N-methylpyrrolidone, tolueneand dimethylformamide are preferred.

There are no particular restrictions on the copper catalyst used so longas it can yield the target compound and does not produce any unseparableby-products, and specifically there may be mentioned copper (powder),copper(I) chloride, copper(II) chloride, copper(I) iodide, copper(I)oxide, copper(II) oxide, copper(II) acetate, copper(II) sulfatepentahydrate, copper(II) acetylacetonate, copper(I) thiocyanate and thelike, among which copper (powder) and copper(I) chloride are preferred.

There are no particular restrictions on the ligand used so long as itcan yield the target compound and does not produce any unseparableby-products, and specifically there may be mentioned ethylene glycol,diethylene glycol, cresol, 2,6-dimethylphenol, 1-naphthol, 2-naphthol,ethylenediamine, N,N′-dimethylethylenediamine and diisopropylamine,among which ethylene glycol and ethylenediamine are preferred.

There are no particular restrictions on the base used so long as it canyield the target compound and does not produce any unseparableby-products, and specifically there may be mentioned inorganic basessuch as sodium t-butoxide, potassium t-butoxide, tripotassium phosphate,trisodium phosphate, cesium carbonate, potassium carbonate, sodiumcarbonate and sodium hydride, or organic bases such as potassiumbis(trimethylsilyl)amide, among which potassium carbonate andtripotassium phosphate are preferred.

The reaction temperature will differ depending on the startingmaterials, solvent and reagents, but will usually be between 0° C. and250° C., and is preferably between 80° C. and 150° C.

The reaction time will differ depending on the starting materials,solvent, reagents and reaction temperature, but will usually be 0.1 to100 hours, and is preferably 0.5 to 48 hours. When the reaction iscarried out in an inert gas atmosphere, the inert gas is notparticularly restricted so long as it does not inhibit the reaction ofthis step, and specifically it may be argon or nitrogen gas.

As supplementary literature to be used as reference for carrying outthis method, there may be mentioned, but not limited to, L. Buchwald etal., Org. Lett. (2002), 4, 581.

Compound (1A) of the invention may be isolated or purified from thereaction mixture obtained above, by the method described below.

When R10 of the resultant compound (1A) is optionally substituted 5- to10-membered cycloalkenyl, it may be subjected to the hydrogenationdescribed above in Method A to yield compound (1A) of the inventionwherein R10 is 5- to 10-membered cycloalkyl optionally substituted withthe corresponding substituent.

When the resultant compound is to be converted to an acid salt, this maybe carried out by a conventional method. The step of producing the saltand the step of hydrogenation may be carried out in a different orderwhere appropriate.

Method G is a method of producing compound (1A) of the invention (thecompound according to the formula (1) above wherein X1 is nitrogen) byreacting compound (8) with compound (10) in an inert solvent, in thepresence of a copper catalyst, in the presence of a base, in thepresence or in the absence of oxygen, and optionally removing protectinggroups on the resultant compound.

In this scheme, R10, R20, R21, R22, R23, R30, R31, R32, R40, n, R10a,R20a, R21a, R22a, R23a, R30a, R31a, R32a and R40a have the samedefinitions as above. M1a is a group represented by the formula—B(OH)_(2.)

There are no particular restrictions on the solvent used so long as itdissolves the starting compound to some extent and does not inhibit thereaction of this step, and specifically there may be mentioned amidessuch as formamide, dimethylformamide, dimethylacetamide,hexamethylphosphoric triamide and N-methylpyrrolidone, halogenatedhydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane andcarbon tetrachloride, aromatic hydrocarbons such as toluene, benzene andxylene or ethers such as diethyl ether, diisopropyl ether,tetrahydrofuran, dioxane, dimethoxyethane and diethyleneglycol dimethylether, or mixtures of these solvents, among which halogenatedhydrocarbons (particularly dichloromethane) are preferred.

There are no particular restrictions on the copper catalyst used so longas it can yield the target compound and does not produce any unseparableby-products, and specifically there may be mentioned copper(II) acetate,copper(I) acetate, copper(II) trifluoromethanesulfonate and copper(II)isobutyrate, among which copper(II) acetate is preferred.

There are no particular restrictions on the base used so long as it canyield the target compound and does not produce any unseparableby-products, and specifically there may be mentioned organic bases suchas triethylamine, pyridine, 2,6-lutidine, N-methylmorpholine and1,8-diazabicyclo[5.4.0]undec-7-ene, among which triethylamine orpyridine is preferred.

There are no particular restrictions on the additive used to acceleratethe reaction so long as it can yield the target compound and does notproduce any unseparable by-products, and specifically there may bementioned molecular sieve, pyridine-N-oxide and2,2,6,6-tetramethylpiperidinooxy, among which molecular sieve(particularly 4 Å) is preferred.

The reaction temperature will differ depending on the startingmaterials, solvent and reagents, but will usually be between 0° C. and80° C., and is preferably between 10° C. and 50° C.

The reaction time will differ depending on the starting materials,solvent, reagents and reaction temperature, but will usually be 1 to 100hours, and is preferably 24 to 48 hours.

Compound (1A) of the invention may be isolated or purified from thereaction mixture obtained in the manner described above, by thefollowing method.

When R10 of the resultant compound (1A) is optionally substituted 5- to10-membered cycloalkenyl, it may be subjected to the hydrogenationdescribed above in Method A to yield compound (1A) of the inventionwherein R10 is 5- to 10-membered cycloalkyl optionally substituted withthe corresponding substituent.

When the resultant compound is to be converted to an acid salt, this maybe carried out by a conventional method. The step of producing the saltand the step of hydrogenation may be carried out in a different orderwhere appropriate.

Method H is a method of producing compound (1A) of the invention (thecompound according to the formula (1) above wherein X1 is nitrogen) byreacting compound (11) with compound (12) in an inert solvent or in theabsence of a solvent, under or not under an inert gas atmosphere, in thepresence or in the absence of a base, in the presence or in the absenceof an additive, and optionally removing protecting groups on theresultant compound.

In this scheme, R10, R20, R21, R22, R23, R30, R31, R32, R40, n, W1,R10a, R20a, R21a, R22a, R23a, R30a, R31a, R32a and R40a have the samedefinitions as above.

There are no particular restrictions on the solvent used so long as itdissolves the starting compound to some extent and does not inhibit thereaction of this step, and specifically there may be mentioned alcoholssuch as methanol, ethanol, n-propanol, isopropanol, n-butanol,isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin,octanol, cyclohexanol and methylcellosolve, aromatic hydrocarbons suchas benzene, chlorobenzene, 1,2-dichlorobenzene, toluene and xylene,ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran,dioxane, dimethoxyethane and diethyleneglycol dimethyl ether, and amidessuch as dimethylformamide, dimethylacetamide, hexamethylphosphorictriamide and N-methylpyrrolidone, among which butanol,1,2-dichlorobenzene, toluene, xylene, tetrahydrofuran, dioxane,dimethylformamide or hexamethylphosphoric triamide is preferred.

When no solvent is used, the reaction may be carried out using amicrowave reactor or with alumina or silica gel as a carrier.

When the reaction is carried out under an atmosphere of an inert gas,there are no particular restrictions on the inert gas so long as it doesnot inhibit the reaction of this step, and specifically there may bementioned argon or nitrogen gas.

There are no particular restrictions on the base used so long as it canyield the target compound and does not produce any unseparableby-products, and specifically there may be mentioned organic bases suchas triethylamine, pyridine, diisopropylethylamine,4-dimethylaminopyridine, DBU and DABCO, or inorganic bases such aspotassium carbonate, sodium carbonate and sodium hydrogencarbonate.

There are no particular restrictions on the additive used to acceleratethe reaction so long as it can yield the target compound and does notproduce any unseparable by-products, and specifically there may bementioned alkali metal iodides such as sodium iodide and potassiumiodide.

The reaction temperature will differ depending on the startingmaterials, solvent and reagents, but will usually be between 0° C. and270° C.

The reaction time will differ depending on the starting materials,solvent, reagents and reaction temperature, but will usually be 0.5 to100 hours.

Compound (1A) of the invention may be isolated or purified from thereaction mixture obtained above, by the method described below.

When R10 of the resultant compound (1A) is optionally substituted 5- to10-membered cycloalkenyl, it may be subjected to the hydrogenationdescribed above in Method A to yield compound (1A) of the inventionwherein R10 is 5- to 10-membered cycloalkyl optionally substituted withthe corresponding substituent.

When the resultant compound is to be converted to an acid salt, this maybe carried out by a conventional method. The step of producing the saltand the step of hydrogenation may be carried out in a different orderwhere appropriate.

Method K is a method of producing compound (1A) of the invention (thecompound according to the formula (1) wherein X1 is nitrogen) byreacting compound (113) with a boron metal reagent (14) or a tin metalreagent (14) (Suzuki reaction or Stille reaction) in an inert solvent,in the presence of a palladium(0) catalyst, under or not under an inertgas atmosphere, in the presence or in the absence of a base, in thepresence or in the absence of an additive, and optionally removingprotecting groups on the resultant compound, or a method of producingcompound (100) of the invention by reacting compound (190) in a similarmanner.

In this scheme, R10, R20, R21, R22, R23, R30, R31, R32, R40, n, W1a,R20a, R21a, R22a, R23a, R30a, R31a, R32a and R40a have the samedefinitions as above. R10b represents optionally substituted 5- to10-membered cycloalkenyl, where the substituent may be protected and hasthe same definition as the substituent of the “optionally substituted 5-to 10-membered cycloalkenyl” for R10.

Also, M1b represents the group B(OE^(10c))₂ or Sn(E^(10b))₃, whereinE^(10c) represents C1-6 alkyl or the two of E^(10c) bond together toform C2-3 alkylene optionally substituted with methyl, and E1brepresents C1-6 alkyl.

This method will differ depending on the nature of M1b.

(Suzuki Coupling Reaction)

This method is a method of producing compound (1A) of the invention (thecompound according to the formula (1) wherein X1 is nitrogen) byreacting compound (13) with compound (14) in an inert solvent, in thepresence of a palladium(0) catalyst, in the presence of a base, in thepresence or in the absence of an additive, under or not under an inertgas atmosphere, and optionally removing protecting groups on theresultant compound, or a method of producing compound (100) of theinvention by reacting compound (190) in a similar manner.

There are no particular restrictions on the solvent used so long as itdissolves the starting compound to some extent and does not inhibit thereaction of this step, and specifically there may be mentioned amidessuch as formamide, dimethylformamide, dimethylacetamide,hexamethylphosphoric triamide and N-methylpyrrolidone, aromatichydrocarbons such as toluene, benzene, xylene and mesitylene, etherssuch as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,dimethoxyethane and diethyleneglycol dimethyl ether, alcohols such asmethanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol,t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol,cyclohexanol and methylcellosolve, nitriles such as acetonitrile andisobutyronitrile, sulfoxides such as dimethylsulfoxide and sulfolane, orwater, or mixtures of these solvents, among which dimethylformamide,toluene, xylene, tetrahydrofuran, dioxane, dimethoxyethane or water, ormixtures of these solvents, are preferred.

There are no particular restrictions on the palladium(0) catalyst usedso long as it can yield the target compound and does not produce anyunseparable by-products, and specifically there may be mentionedtetrakis(triphenylphosphine)palladium,tris(dibenzylideneacetone)dipalladium,bis(dibenzylideneacetone)palladium, bis(tri-t-butylphosphine)palladium,palladium black and the like, or palladium(0) catalysts produced in thereaction system by combination of the palladium complexes which can bepalladium(0) precursors mentioned below and various ligands mentionedbelow.

There are no particular restrictions on various palladium complexeswhich can be used as palladium(0) precursor, so long as they can yieldthe target compound without producing any unseparable by-products, andspecifically there may be mentioned palladium acetate,1,1′-bis(diphenylphosphino)ferrocene dichloropalladium,dichlorobis(tri-o-tolylphosphine)palladium,dichlorobis(triscyclohexylphosphine)palladium, and the like.

There are no particular restrictions on ligands used so long as they canyield the target compound without producing any unseparable by-products,and specifically there may be mentioned triphenylphosphine,tri-t-butylphosphine, tri(4-methylphenyl)phosphine,2-(di-t-butylphosphino)biphenyl, 2-(dicyclohexylphosphino)biphenyl,tricyclohexylphosphine, 1,1′-bis(diphenylphosphino)ferrocene anddi-t-butylphosphonium tetrafluoroborate.

There are no particular restrictions on the base used so long as it canyield the target compound and does not produce any unseparableby-products, and specifically there may be mentioned inorganic basessuch as tripotassium phosphate, trisodium phosphate, cesium carbonate,potassium carbonate, sodium carbonate, cesium bicarbonate, potassiumhydrogencarbonate, sodium hydrogencarbonate, sodium acetate, bariumhydroxide, potassium hydroxide, potassium fluoride and cesium fluoride,metal alkoxides such as sodium ethoxide and sodium-t-butoxide, alkalimetal acetate such as sodium acetate or potassium acetate, or organicbases such as triethylamine.

There are no particular restrictions on the additive used so long as itcan yield the target compound and does not produce any unseparableby-products, and specifically there may be mentioned lithium chloride,sodium chloride, lithium bromide, sodium bromide and tetrabutylammoniumbromide.

The reaction temperature will differ depending on the startingmaterials, solvent and reagents, but will usually be between 0° C. and150° C., and is preferably between 20° C. and 120° C.

The reaction time will differ depending on the starting materials,solvent, reagents and reaction temperature, but will usually be 0.5 to100 hours, and is preferably 0.5 to 48 hours. When the reaction iscarried out in an inert gas atmosphere, the inert gas is notparticularly restricted so long as it does not inhibit the reaction ofthis step, and specifically it may be argon or nitrogen gas.

As supplementary literature to be used as reference for carrying outthis method, there may be mentioned, but not limited to, S. P.Stanforth, Tetrahedron (1998), 54, 263. and N. Miyaura, A. Suzuki, Chem.Rev. (1995), 95, 2457.

(Stille Coupling Reaction)

This method is a method of producing compound (1A) of the invention (thecompound according to the formula (1) wherein X1 is nitrogen) byreacting compound (13) with compound (14) in an inert solvent, in thepresence of a palladium(0) catalyst, in the presence or in the absenceof an additive, under or not under an inert gas atmosphere, andoptionally removing protecting groups on the resultant compound, or amethod of producing compound (100) of the invention by reacting compound(190) in a similar manner.

There are no particular restrictions on the solvent used so long as itdissolves the starting compound to some extent and does not inhibit thereaction of this step, and specifically there may be mentioned amidessuch as dimethylformamide, dimethylacetamide, hexamethylphosphorictriamide and N-methylpyrrolidone, aromatic hydrocarbons such as toluene,benzene, xylene and mesitylene, ethers such as diethyl ether,diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane anddiethyleneglycol dimethyl ether, or mixtures of these solvents, amongwhich dimethylformamide, toluene, xylene, tetrahydro furan, dioxane anddimethoxyethane are preferred.

There are no particular restrictions on the palladium(0) catalyst usedso long as it can yield the target compound and does not produce anyunseparable by-products, and specifically there may be mentionedtetrakis(triphenylphosphine)palladium,tris(dibenzylideneacetone)dipalladium,bis(dibenzylideneacetone)palladium, bis(tri-t-butylphosphine)palladium,palladium black and the like, or palladium(0) catalysts produced in thereaction system by combination of the palladium complexes which can bepalladium(0) precursors mentioned below and various ligands mentionedbelow.

There are no particular restrictions on various palladium complexeswhich can be used as palladium(0) precursors, so long as they can yieldthe target compound without producing any unseparable by-products, andspecifically there may be mentioned palladium acetate,1,1′-bis(diphenylphosphino)ferrocene dichloropalladium,dichlorobis(tri-o-tolylphosphine)palladium,dichlorobis(acetonitrile)palladium anddichlorobis(triscyclohexylphosphine)palladium.

There are no particular restrictions on ligands used so long as they canyield the target compound without producing any unseparable by-products,and specifically there may be mentioned triphenylphosphine,tri-t-butylphosphine, tri(4-methylphenyl)phosphine,2-(di-t-butylphosphino)biphenyl, 2-(dicyclohexylphosphino)biphenyl,tricyclohexylphosphine, tri-2-furylphosphine,1,1′-bis(diphenylphosphino)ferrocene, di-t-butylphosphoniumtetrafluoroborate and triphenylarsine.

There are no particular restrictions on the additive used so long as itcan yield the target compound and does not produce any unseparableby-products, and specifically there may be mentioned cesium fluoride,potassium fluoride, lithium chloride, lithium bromide, sodium bromide,tetrabutylammonium fluoride, copper iodide, copper oxide and zincchloride.

The reaction temperature will differ depending on the startingmaterials, solvent and reagents, but will usually be between 0° C. and150° C., and is preferably between 20° C. and 110° C.

The reaction time will differ depending on the starting materials,solvent, reagents and reaction temperature, but will usually be 0.1 to100 hours, and is preferably 0.5 to 48 hours.

When the reaction is carried out in an inert gas atmosphere, the inertgas is not particularly restricted so long as it does not inhibit thereaction of this step, and specifically it may be argon or nitrogen gas.

As supplementary literature to be used as reference for carrying outthis method, there may be mentioned, but not limited to, S. P.Stanforth, Tetrahedron (1998), 54, 263 and J. K. Stille, Angew. Chem.Int. Ed. Engl. (1986), 25, 508.

Compounds (1A) and (100) of the invention may be isolated or purifiedfrom the reaction mixture obtained above, by the method described below.

When R10 of the resultant compounds (1A) and (100) is optionallysubstituted 5- to 10-membered cycloalkenyl, it may be subjected to thehydrogenation described above in Method A to yield compound (1A) of theinvention or compound (1B) of the invention (the compound (1) wherein X1is CH) wherein R10 is 5- to 10-membered cycloalkyl optionallysubstituted with the corresponding substituent.

When R10 of the resultant compound (100) is optionally substituted 5- to10-membered cycloalkyl, it may be subjected to hydrogenation to yieldcompound (1B) (the compound (1) wherein X1 is CH) of the invention.

When the resultant compound is to be converted to an acid salt, this maybe carried out by a conventional method. The step of producing the saltand the step of hydrogenation may be carried out in a different orderwhere appropriate.

Method M is a method of producing compound (1A) of the invention (thecompound according to the formula (1) wherein X1 is nitrogen) byreacting compound (16) with a boron metal reagent (15) or tin metalreagent (15) (Suzuki reaction or Stille reaction) in an inert solvent,in the presence of a palladium(0) catalyst, under or not under an inertgas atmosphere, in the presence or in the absence of a base, in thepresence or in the absence of an additive, and optionally removingprotecting groups on the resultant compound, or a method of producingcompound (100) of the invention by reacting compound (180) in a similarmanner.

In this scheme, R10, R20, R21, R22, R23, R30, R31, R32, R40, n, W1a,R20a, R21a, R22a, R23a, R30a, R31a, R32a and R40a have the samedefinitions as above. R10b also has the same definition as above.

M1 represents the group B(OE^(10a))₂ or Sn(E^(10b))₃, wherein E^(10a)represents hydrogen, C1-6 alkyl or the two of E^(10a) bond together toform C2-3 alkylene optionally substituted with methyl, and E^(10b)represents C1-6 alkyl.

This method may be carried out in a manner similar to Method K describedabove.

Compounds (1A) and (100) of the invention may be isolated or purifiedfrom the reaction mixture obtained above, by the method described below.

When R10 of the resultant compounds (1A) and (100) is optionallysubstituted 5- to 10-membered cycloalkenyl, it may be subjected to thehydrogenation described above in Method A to yield compound (1A) of theinvention or compound (1B) of the invention (the compound (1) wherein X1is CH) wherein R10 is 5- to 10-membered cycloalkyl optionallysubstituted with the corresponding substituent.

When R10 of the resultant compound (100) is optionally substituted 5- to10-membered cycloalkyl, it may be subjected to hydrogenation to yieldcompound (1B) (the compound (1) wherein X1 is CH) of the invention.

When the resultant compound is to be converted to an acid salt, this maybe carried out by a conventional method. The step of producing the saltand the step of hydrogenation may be carried out in a different orderwhere appropriate.

Method N is a method of producing compound (1) of the invention byreacting compound (17) with a halogenating reagent in an inert solvent,in the presence or in the absence of an additive, in the presence or inthe absence of an inert gas, to yield a compound halogenated on thebenzene ring to which R10a is bonded (Step N-1-1), and optionallyremoving protecting groups on the resultant compound.

Alternatively, (Step N-1-1) may be followed by reaction of thehalogenated compound with a compound which can introduce a desiredsubstituent, or a reactive derivative thereof, in the presence of atransition metal catalyst, in an inert solvent, in the presence or inthe absence of an additive, in the presence or in the absence of aninert gas (Step N-1-2), and optionally removing any protecting groups onthe resultant compound, to produce compound (1) of the invention.

In this scheme, R10, R20, R21, R22, R23, R30, R31, R32, R40, n, X1,R10a, R30a, R31a, R32a and R40a have the same definitions as above.Also, at least one of R20b, R21b, R22b and R23b is hydrogen, and theremaining groups are groups corresponding to R20a, R21a, R22a and R23a,respectively.

(Step N-1-1)

This is a halogenating step.

There are no particular restrictions on the solvent used so long as itdissolves the starting compound to some extent and does not inhibit thereaction of this step, and specifically there may be mentioned alcoholssuch as methanol, ethanol, n-propanol, isopropanol, n-butanol,isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin,octanol, cyclohexanol and methylcellosolve, aliphatic hydrocarbons suchas hexane, heptane, ligroin and petroleum ether, ethers such as dioxane,dimethoxyethane and diethyleneglycol dimethyl ether, halogenatedhydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane andcarbon tetrachloride, ethers such as diethyl ether, diisopropyl ether,tetrahydrofuran, dioxane, dimethoxyethane and diethyleneglycol dimethylether, amides such as formamide, dimethylformamide, dimethylacetamideand hexamethylphosphoric triamide, and organic acids such as aceticacid, among which alcohols (particularly methanol) are preferred.

There are no particular restrictions on the halogenating agent used solong as it can yield the target compound and does not produce anyunseparable by-products, and specifically there may be mentionedchlorine (Cl₂), bromine (Br₂), iodine (I₂), N-chlorosuccinimide,N-bromosuccinimide, N-iodosuccinimide, iodine monochloride and thionylchloride, among which chlorine, bromine and iodine are preferred.

As additives to be used there may be mentioned alkali metal acetate suchas sodium acetate and potassium acetate, among which sodium acetate ispreferred.

The reaction temperature will differ depending on the startingmaterials, solvent and reagents, but will usually be between −20° C. and100° C., and is preferably between 20° C. and 50° C.

The reaction time will differ depending on the starting materials,solvent, reagents and reaction temperature, but will usually be 0.25 to48 hours, and is preferably 12 to 24 hours.

Compound (1) of the invention may be isolated or purified from thereaction mixture obtained above, by the method described below.

When R10 of the resultant compound (1) is optionally substituted 5- to10-membered cycloalkenyl, the hydrogenation described above in Method Amay be carried out by selecting the reaction conditions so as to avoidreducing the introduced halogen, to yield compound (1) of the inventionwherein R10 is 5- to 10-membered cycloalkyl optionally substituted withthe corresponding substituent.

When the resultant compound is to be converted to an acid salt, this maybe carried out by a conventional method. The step of producing the saltand the step of hydrogenation may be carried out in a different orderwhere appropriate.

(Step N-1-2)

In this step, the halogenated compound obtained in Step N-1-1 isconverted to a compound having a desired substituent in the presence ofa transition metal catalyst, and protecting groups on the resultantcompound are optionally removed by the method described below, toproduce compound (1) of the invention.

The aryl halide compound obtained in Step N-1-1 may then be subjected tocross coupling reaction with a compound which can introduce a desiredsubstituent or a reactive derivative thereof, in the presence of atransition metal such as palladium, copper, nickel, zinc or zirconium,or a catalyst comprising a combination of any of these metals with aligand. The bond formation reaction type may be carbon-carbon bondformation, carbon-nitrogen bond formation or carbon-oxygen bondformation. Method F and Method K are examples of these reactions, and assupplementary literature to be used as reference for carrying out thisstep there may be mentioned, but not limited to, John F. Hartwig; Angew.Chem. Int. Ed.; (1998), 37, 2046., Steven P. Nolan, et al.; Org. Lett.(2001), 3, 10, 1511., Stephen L. Buchwald and Gregory C. Fu, et al.;Org. Lett. (2000), 2, 12, 1729., Stephen P. Stanforth; Tetrahedron(1998), 54, 263., Karen, E. et. al.; J.A.C.S. (2001), 123, 10770.,Stephen L. Buchwald, et. al.; J.A.C.S. (1999), 121, 4369., D. M. Tschaenand R. Desmond, et al.; Synth. Comm. (1994), 24, 6, 887., John F.Hartwig, et. al.; J.A.C.S. (2001), 123, 8410., Gregory C. Fu, et al.;Org. Lett. (2001), 3, 26, 4295., Damien Prim, et al.; and Tetrahedron(2002), 58, 2041.

For example, introduction of morpholine as a substituent in acarbon-nitrogen bond formation reaction may be carried out in thefollowing manner.

There are no particular restrictions on the solvent used so long as itdissolves the starting compound to some extent and does not inhibit thereaction of this step, and specifically there may be mentioned aromatichydrocarbons such as benzene, toluene and xylene, ethers such asdioxane, dimethoxyethane and tetrahydrofuran, and amides such asdimethylformamide, among which xylene is preferred.

There are no particular restrictions on the additive used so long as itcan yield the target compound and does not produce any unseparableby-products, and it may be appropriately selected from among palladiumcatalysts such as palladium(II) acetate, bases such as potassiumt-butoxide, sodium t-butoxide and cesium carbonate, and phosphines suchas 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl andtri-t-butylphosphonium tetrafluoroborate, among which a combination ofpalladium(II) acetate, sodium t-butoxide and tri-t-butylphosphoniumtetrafluoroborate is preferred.

The reaction temperature will differ depending on the startingmaterials, solvent and reagents, but will usually be between 50° C. and200° C., and is preferably between 70° C. and 150° C.

The reaction time will differ depending on the starting materials,solvent, reagents and reaction temperature, but will usually be 0.5 to72 hours, and is preferably 2 to 24 hours.

Compound (1) of the invention may be isolated or purified from thereaction mixture obtained above, by the following method.

When R10 of the resultant compound (1) is optionally substituted 5- to10-membered cycloalkenyl, it may be subjected to the hydrogenationdescribed above in Method A to yield compound (1) of the inventionwherein R10 is 5- to 10-membered cycloalkyl optionally substituted withthe corresponding substituent.

When the resultant compound is to be converted to an acid salt, this maybe carried out by a conventional method. The step of producing the saltand the step of hydrogenation may be carried out in a different orderwhere appropriate.

Method P is a method of producing compound (1) of the invention byreacting compound (18) with a trifluoromethanesulfonylating agent in aninert solvent, to yield a compound wherein the phenolic hydroxyl hasbeen trifluoromethanesulfonylated (Step P-1-1), and optionally removingprotecting groups on the resultant compound, or alternatively, (StepP-1-1) may be followed by reaction with a compound which can introduce adesired substituent into the phenyltriflate compound, or a reactivederivative thereof (Step P-1-2), and optionally removal of protectinggroups on the resultant compound, to produce compound (1) of theinvention.

This method may be carried out when a phenolic hydroxyl group is presenton the benzene ring to which R10a is bonded.

In this scheme, R10, R20, R21, R22, R23, R30, R31, R32, R40, n, X1,R10a, R30a, R31a, R32a and R40a have the same definitions as above.Also, one of R20c, R21c, R22c and R23c is a phenolic hydroxyl group,while the remaining groups correspond to R20a, R21a, R22a and R23a,respectively.

(Step P-1-1)

This step may be carried out in a manner similar to the sulfonylationdescribed in Method A or Method B above. Trifluoromethanesulfonylationmay be replaced by nonafluorobutanesulfonylation ortoluenesulfonylation.

Compound (1) of the invention may be isolated or purified from thereaction mixture obtained above, by the method described below.

When R10 of the resultant compound (1) is optionally substituted 5- to10-membered cycloalkenyl, it may be subjected to the hydrogenationdescribed above in Method A to yield compound (1) of the inventionwherein R10 is 5- to 10-membered cycloalkyl optionally substituted withthe corresponding substituent.

When the resultant compound is to be converted to an acid salt, this maybe carried out by a conventional method. The step of producing the saltand the step of hydrogenation may be carried out in a different orderwhere appropriate.

(Step P-1-2)

This is a step of converting the trifluoromethanesulfonyloxy group ofthe compound obtained in Step P-1-1 to a desired substituent.

This step may be carried out in a manner similar to Method N-1-2described above. As supplementary literature to be used as reference forcarrying out this method, there may be mentioned, but not limited to,Kurt Ritter; Synthesis, (1993), 735.

Compound (1) of the invention may be isolated or purified from thereaction mixture obtained above, by the method described below.

When R10 of the resultant compound (1) is optionally substituted 5- to10-membered cycloalkenyl, it may be subjected to the hydrogenationdescribed above in Method A to yield compound (1) of the inventionwherein R10 is 5- to 10-membered cycloalkyl optionally substituted withthe corresponding substituent.

When the resultant compound is to be converted to an acid salt, this maybe carried out by a conventional method. The step of producing the saltand the step of hydrogenation may be carried out in a different orderwhere appropriate.

Method Q is a method of producing compound (1A) of the invention (thecompound according to the formula (1) wherein X1 is nitrogen) byreacting compound (19) and compound (20) in an inert solvent, in thepresence of a reducing agent, in the presence or in the absence of anacid, in the presence of an additive, and optionally removing protectinggroups on the resultant compound.

In this scheme, R10, R20, R21, R22, R23, R30, R31, R32, R40, n, W1,R10a, R20a, R21a, R22a, R23a and R40a have the same definitions asabove. Also, E1, E2 and E3 are groups suitable for obtaining the desiredgroup of the formula:

Substituents on E1, E2 or E3 may optionally be protected.

This method may be carried out in a manner similar to Method C describedabove.

Compound (1A) of the invention may be isolated or purified from thereaction mixture obtained above, by the method described below.

When R10 of the resultant compound (1A) is optionally substituted 5- to10-membered cycloalkenyl, it may be subjected to the hydrogenationdescribed above in Method A to yield compound (1A) of the inventionwherein R10 is 5- to 10-membered cycloalkyl optionally substituted withthe corresponding substituent.

When the resultant compound is to be converted to an acid salt, this maybe carried out by a conventional method. The step of producing the saltand the step of hydrogenation may be carried out in a different orderwhere appropriate.

Method R is a method of producing compound (1A) of the invention (thecompound according to the formula (1) wherein X1 is nitrogen) byreacting compound (21) with a base in an inert solvent, and optionallyremoving protecting groups on the resultant compound.

In this scheme, R10, R20, R21, R22, R23, R30, R31, R32, R40, n, W1,R10a, R20a, R21a, R22a, R23a and R40a have the same definitions asabove. Also, E4, E5 and E6 are groups suitable for obtaining the desiredgroup of the formula:

Substituents on E4, E5 or E6 may optionally be protected.

This method may be carried out in a manner similar to Method A describedabove.

Compound (1A) of the invention may be isolated or purified from thereaction mixture obtained above, by the method described below.

When R10 of the resultant compound (1A) is optionally substituted 5- to10-membered cycloalkenyl, it may be subjected to the hydrogenationdescribed above in Method A to yield compound (1A) of the inventionwherein R10 is 5- to 10-membered cycloalkyl optionally substituted withthe corresponding substituent.

When the resultant compound is to be converted to an acid salt, this maybe carried out by a conventional method. The step of producing the saltand the step of hydrogenation may be carried out in a different orderwhere appropriate.

Method S is a method of producing compound (1B) of the invention (thecompound according to the formula (1) wherein X1 is CH) by reacting apalladium(0) catalyst, compound (22) and compound (9) in an inertsolvent, and then hydrogenating the product and optionally removingprotecting groups on the compound (Method S-1) or a method of producingcompound (100) of the invention by reacting compounds (22) and (9) inthe same manner and optionally removing protecting groups on theresultant compound (Method S-2), and a method of leading to compound(1B) of the invention further by hydrogenation if necessary (MethodS-3).

In this scheme, R10, R20, R21, R22, R23, R30, R31, R32, R40, n, W1a,M1b, R10a, R20a, R21a, R22a, R23a, R30a, R31a, R32a and R40a have thesame definitions as above.

This method may be carried out in a manner similar to Method K describedabove, followed by hydrogenation reaction in a manner similar to MethodA above.

Compound (1B) and (100) of the invention may be isolated or purifiedfrom the reaction mixture obtained above, by the method described below.

When the resultant compound is to be converted to an acid salt, this maybe carried out by a conventional method. The step of producing the saltand the step of hydrogenation after reaction between compound (22) andcompound (9) may be carried out in a different order where appropriate.

Method T is a method of producing compound (1B) of the invention (thecompound according to the formula (1) wherein X1 is CH) by reactingcompound (24) and compound (25) in an inert solvent, in the presence ofa palladium(0) catalyst, and then hydrogenating the product andoptionally removing protecting groups on the resultant compound (MethodT-1), or a method of producing compound (100) of the invention byreacting compounds (24) and (25) in the same manner and optionallyremoving protecting groups on the resultant compound (Method T-2), and amethod of leading to compound (1B) of the invention further byhydrogenation if necessary (Method T-3).

In this scheme, R10, R20, R21, R22, R23, R30, R31, R32, R40, n, W1a, M1,R10b, R20a, R21a, R22a, R23a, R30a, R31a, R32a and R40a have the samedefinitions as above.

This method may be carried out in a manner similar to Method K describedabove, followed by hydrogenation reaction in a manner similar to MethodA above.

Compounds (1B) and (100) of the invention may be isolated or purifiedfrom the reaction mixture obtained above, by the method described below.

When the resultant compound is to be converted to an acid salt, this maybe carried out by a conventional method. The step of producing the saltand the step of hydrogenation after reaction between compound (24) andcompound (25) may be carried out in a different order where appropriate.

Method U is a method of producing compound (1B) of the invention (thecompound according to the formula (1) wherein X1 CH) by reactingcompound (26) with compound (27) (i.e. a lithium reagent or Grignardreagent) in an inert solvent to yield an adduct (170) (Step U-1-1), andthen reducing the hydroxyl at the benzyl position of the resultantadduct (170) (Step U-1-2), and optionally removing protecting groups, ora method of producing compound (100) of the invention by the reaction inthe same manner to yield an adduct (170) (Step U-1-1), then dehydratingthe hydroxyl of the adduct (170) in the presence of or in the absence ofacid (Step U-1-3), and further removing protecting groups if necessary.

In this scheme, R10, R20, R21, R22, R23, R30, R31, R32, R40, n, R10b,R20a, R21a, R22a, R23a, R30a, R31a, R32a and R40a have the samedefinitions as above. M2 is a lithium or magnesium halide.

(Step U-1-1)

There are no particular restrictions on the solvent used so long as itdissolves the starting compound to some extent and does not inhibit thereaction of this step, and specifically there may be mentioned etherssuch as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,dimethoxyethane and diethyleneglycol dimethyl ether, among whichtetrahydrofuran is preferred.

The reaction temperature will differ depending on the startingmaterials, solvent and reagents, but will usually be between −80° C. and30° C.

The reaction time will differ depending on the starting materials,solvent, reagents and reaction temperature, but will usually be 0.25 to6 hours.

(Step U-1-2)

This step may be carried out by reduction in a manner similar to thehydrogenation described in Method A above, or by reduction using atrialkylsilyl hydride described hereunder, although there is nolimitation to these methods.

There are no particular restrictions on the solvent used so long as itdissolves the starting compound to some extent and does not inhibit thereaction of this step, and specifically there may be mentioned, in thecase of reduction reaction using a trialkylsilyl hydride, halogenatedhydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane andcarbon tetrachloride (particularly dichloromethane).

There are no particular restrictions on the reducing agents used so longas it can yield the target compound and does not produce any unseparableby-products, and specifically there may be mentioned trialkylsilylhydrides such as triethylsilyl hydride and triisopropylsilyl hydride,among which triethylsilyl hydride is preferred.

There are no particular restrictions on the additive used so long as itcan yield the target compound and does not produce any unseparableby-products, and specifically there may be mentioned halo-substitutedacetic acids such as trifluoroacetic acid, and Lewis acids such as borontrifluoride.

The reaction temperature will differ depending on the startingmaterials, solvent and reagents, but will usually be between −70° C. and50° C.

The reaction time will differ depending on the starting materials,solvent, reagents and reaction temperature, but will usually be 0.5 to48 hours.

(Step U-1-3)

There are no particular restrictions on the solvent used so long as itdissolves the starting compound to some extent and does not inhibit thereaction of this step, and specifically there may be mentioned, etherssuch as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane anddiethyleneglycol dimethylether, aromatic hydrocarbons such as toluene,benzene and xylene, halogenated hydrocarbons such as chloroform,dichloromethane, 1,2-dichloroethane and carbon tetrachloride, water, andthe mixed solvent thereof, or without solvent.

There are no particular restrictions on the reducing agents used so longas it can yield the target compound and does not produce any unseparableby-products, and specifically there may be mentioned trialkylsilylhydrides such as triethylsilyl hydride and triisopropylsilyl hydride,among which triethylsilyl hydride is preferred, and tetrahydrofuran,toluene, dichloromethane, chloroform or water is preferred.

There are no particular restrictions on the acid additive used so longas it can yield the target compound and does not produce any unseparableby-products, and specifically there may be mentioned halo-substitutedacetic acids such as trifluoroacetic acid, Lewis acids such as borontrifluoride, organic sulfonic acids such as toluenesulfonic acid andcamphor sulfonic acid, and inorganic acids such as hydrochloric acid andhydrogen bromide.

The reaction temperature will differ depending on the startingmaterials, solvent and reagents, but will usually be between −80° C. and180° C.

The reaction time will differ depending on the starting materials,solvent, reagents and reaction temperature, but will usually be 0.25 to24 hours.

Compounds (1B) and (100) of the invention may be isolated or purifiedfrom the reaction mixture obtained above, by the method described below.

When R10 of the resultant compound (1B) is optionally substituted 5- to10-membered cycloalkenyl, it may be subjected to the hydrogenationdescribed above in Method A to yield compound (1B) of the inventionwherein R10 is 5- to 10-membered cycloalkyl optionally substituted withthe corresponding substituent.

When the resultant compound is to be converted to an acid salt, this maybe carried out by a conventional method. The step of producing the saltand the step of hydrogenation may be carried out in a different orderwhere appropriate.

Method V is a method of producing compound (1) of the invention byreacting compound (53) with compound (150) (i.e. a lithium reagent orGrignard reagent) in an inert solvent to yield an adduct (140) (StepV-1-1), and then, if necessary, reducing or dehydrating the hydroxyl atthe benzyl position of the resultant adduct (140) (Step V-1-2), andoptionally removing protecting groups, or a method of producing compound(2) by the reaction in the same manner to yield an adduct (140) (StepV-1-1), then, if necessary, reducing or dehydrating the hydroxyl at thebenzyl position of the adduct (140) (Step V-1-3), and further removingprotecting groups.

In this scheme, R10, R20, R21, R22, R23, R30, R31, R32, R40, X1, n,R10a, R20a, R21a, R22a, R23a, R30a, R31a and R32a have the samedefinitions as above. M2 is a lithium or magnesium halide. R200 has thesame definition as substituents included in Group A1 above, orrepresents the substituents, the substituents thereon being protected. uis an integer of 0, 1, 2, 3, 4 or 5. k is an integer of 0, 1, 2, 3, 4 or5. PR40a has the same definition as R40a above or represents protectinggroup for amino (preferably, t-butoxycarbonyl or benzyl).

This method may be performed in a manner similar to Method U andsubsequently hydrogenation described in Method A.

Compound (1) of the invention and compound (2) may be isolated orpurified from the reaction mixture obtained above, by the methoddescribed below.

When R10 of the resultant compound (1) is optionally substituted 5- to10-membered cycloalkenyl, it may be subjected to the hydrogenationdescribed above in Method A to yield compound (1) of the inventionwherein R10 is 5- to 10-membered cycloalkyl optionally substituted withthe corresponding substituent.

When the resultant compound is to be converted to an acid salt, this maybe carried out by a conventional method. The step of producing the saltand the step of hydrogenation may be carried out in a different orderwhere appropriate.

Removal of the protecting group(s) will differ depending on their types,and it may be carried out in the following manner, according toprotocols commonly known in the field of synthetic organic chemistrysuch as the protocol described in, for example, T. W. Greene,(Protective Groups in Organic Synthesis) or John Wiley & Sons: J. F. W.McOmis, (Protective Groups in Organic Chemistry), Plenum Press.

When the amino-protecting group is an optionally substituted silyl groupsuch as trimethylsilyl, triethylsilyl, triisopropylsilyl,t-butyldimethylsilyl or t-butyldiphenylsilyl, it will usually be removedby treatment with a fluoride anion-generating compound such astetrabutylammonium fluoride, hydrofluoric acid, hydrofluoricacid-pyridine or potassium fluoride.

The inert solvent used for the reaction is not particularly restrictedso long as it does not inhibit the reaction, and for example, etherssuch as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,dimethoxyethane and diethyleneglycol dimethyl ether are preferred.

There are no particular restrictions on the reaction temperature andreaction time, but normally the reaction temperature will be between 0°C. and 50° C., and the reaction time will be between 10 to 18 hours.

When the amino-protecting group is an optionally substituted aliphaticacyl group, an optionally substituted aromatic acyl group, an optionallysubstituted alkoxycarbonyl group or a substituted methylene group whichforms a Schiff base, it may be removed by treatment with an acid or basein the presence of an aqueous solvent.

The acid used for this reaction is not particularly restricted so longas it is an acid which is ordinarily used for removal of theamino-protecting group, and for example, it may be an inorganic acidsuch as hydrobromic acid, hydrochloric acid, sulfuric acid, perchloricacid, phosphoric acid or nitric acid, or an organic acid such astrifluoroacetic acid and trifluoromethanesulfonic acid, among whichhydrochloric acid or trifluoroacetic acid is preferred.

The base used for this reaction is not particularly restricted so longas it is a base which is ordinarily used for removal of theamino-protecting group, but there are preferably used alkali metalcarbonic acid salts such as lithium carbonate, sodium carbonate andpotassium carbonate; alkali metal hydroxides such as lithium hydroxide,sodium hydroxide and potassium hydroxide; metal alkoxides such aslithium methoxide, sodium methoxide, sodium ethoxide andpotassium-t-butoxide; and ammonia mixtures such as ammonia water andconcentrated ammonia-methanol.

The solvent used for the reaction may be, for example, an alcohol suchas methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol,t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol,cyclohexanol or methylcellosolve; an ether such as diethyl ether,diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane ordiethyleneglycol dimethyl ether; water; or a mixture of water and any ofthe aforementioned solvents, among which alcohols (most preferablyethanol) are preferred.

The reaction temperature and the reaction time will differ depending onthe starting compounds, the solvent and the acid or base used and arenot particularly restricted, but in order to inhibit by-products, thereaction temperature will usually be between 0° C. and 150° C. and thereaction time will usually be 1 to 10 hours.

When the amino-protecting group is an optionally substituted aralkylgroup or an optionally substituted aralkyloxycarbonyl group, a method ofcontact with a reducing agent in an inert solvent (preferably catalyticreduction at ordinary temperature in the presence of a catalyst) or amethod of removal by oxidation is generally preferred.

The inert solvent used for removal by catalytic reduction is notparticularly restricted so long as it is inert to the reaction, and forexample, it may be an aliphatic hydrocarbon such as hexane, heptane,ligroin or petroleum ether; an aromatic hydrocarbon such as toluene,benzene or xylene; an ester such as methyl acetate, ethyl acetate,propyl acetate, butyl acetate or diethyl carbonate; an ether such asdiethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,dimethoxyethane or diethyleneglycol dimethyl ether; an alcohol such asmethanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol,t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol,cyclohexanol or methylcellosolve; an organic acid such as acetic acid;water; or a mixture of any of these solvents with water, among whichalcohols, ethers, organic acids and water (most preferably alcohols andorganic acids) are preferred.

The catalyst used for removal by catalytic reduction is preferablypalladium-carbon, Raney nickel, platinum oxide, platinum-black,rhodium-aluminum oxide, triphenylphosphine-rhodium chloride orpalladium-barium sulfate.

There are no particular restrictions on the pressure, but it willordinarily be from 1 to 10 atmospheres.

The reaction temperature and the reaction time will differ depending onthe starting materials, catalyst and insert solvent, but usually thereaction temperature will be between 0° C. and 100° C., and the reactiontime will be between 5 minutes and 72 hours.

The inert solvent used for removal by oxidation is not particularlyrestricted so long as it does not participate in the reaction, butwater-containing organic solvents are preferred. Such organic solventsinclude, for example, halogenated hydrocarbons such as chloroform,dichloromethane, 1,2-dichloroethane and carbon tetrachloride; nitrilessuch as acetonitrile; ethers such as diethyl ether, diisopropyl ether,tetrahydrofuran, dioxane, dimethoxyethane and diethyleneglycol dimethylether; ketones such as acetone; amides such as formamide,dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide;and sulfoxides such as dimethylsulfoxide and sulfolane, among whichhalogenated hydrocarbons, ethers or sulfoxides (most preferablyhalogenated hydrocarbons and sulfoxides) are preferred.

The oxidizing agent used for this reaction is not particularlyrestricted so long as it is an oxidizing agent used for removal of theamino-protecting group, but it is preferably potassium persulfate,sodium persulfate, ammonium cerium nitrate (CAN) or2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ).

The reaction temperature and the reaction time will differ depending onthe starting compounds, oxidizing agent and solvent, but usually thereaction temperature will be between 0° C. and 150° C., and the reactiontime will be between 10 minutes and 24 hours.

When the amino-protecting group is an optionally substituted aralkylgroup, the protecting group may be removed using an acid or base.

The acid used for this reaction is not particularly restricted so longas it is an acid used for removal of the optionally substituted aralkylgroup as the amino-protecting group, and for example, it may be aBronsted acid, e.g. an inorganic acid such as hydrochloric acid,hydrobromic acid, sulfuric acid, perchloric acid or phosphoric acid, oran organic acid such as acetic acid, formic acid, oxalic acid,methanesulfonic acid, p-toluenesulfonic acid, camphor sulfonic acid,trifluoroacetic acid or trifluoromethanesulfonic acid; a Lewis acid suchas zinc chloride, tin tetrachloride, boron trichloride, borontrifluoride or boron tribromide; or an acidic ion-exchange resin, amongwhich inorganic acids and organic acids (most preferably hydrochloricacid, acetic acid and trifluoroacetic acid) are preferred.

The base used for the reaction is not particularly restricted so long asit is a base ordinarily used for removal of the optionally substitutedaralkyl group as the amino-protecting group, but it is preferably analkali metal carbonate such as lithium carbonate, sodium carbonate orpotassium carbonate; an alkali metal hydroxide such as lithiumhydroxide, sodium hydroxide or potassium hydroxide; a metal alkoxidesuch as lithium methoxide, sodium methoxide, sodium ethoxide orpotassium-t-butoxide; or an ammonia mixture such as aqueous ammonia orconcentrated ammonia-methanol.

The inert solvent used for the first stage of the reaction is notparticularly restricted so long as it is inert to the reaction, and asexamples there may be mentioned aliphatic hydrocarbons such as hexane,heptane, ligroin and petroleum ether; aromatic hydrocarbons such asbenzene, toluene and xylene; halogenated hydrocarbons such aschloroform, dichloromethane, 1,2-dichloroethane and carbontetrachloride; esters such as methyl acetate, ethyl acetate, propylacetate, butyl acetate and diethyl carbonate; ethers such as diethylether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane anddiethyleneglycol dimethyl ether; alcohols such as methanol, ethanol,n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamylalcohol, diethylene glycol, glycerin, octanol, cyclohexanol andmethylcellosolve; amides such as formamide, dimethylformamide,dimethylacetamide and hexamethylphosphoric triamide; water; and mixturesof the aforementioned solvents, among which ethers, alcohols and water(most preferably dioxane, tetrahydrofuran, ethanol or water) arepreferred.

The reaction temperature will differ depending on the starting compoundsand the acid and solvent used, but will ordinarily be between −20° C.and the boiling temperature (preferably between 0° C. and 100° C.).

The reaction time will differ depending on the starting compounds, theacid and inert solvent used and the reaction temperature, but willordinarily be between 15 minutes and 48 hours (preferably between 30minutes and 20 hours).

When the amino-protecting group is an optionally substitutedalkenyloxycarbonyl group, usually the removal may be accomplished bytreatment with an acid or base, under the same conditions as removalreaction when the amino-protecting group is an optionally substitutedaliphatic acyl group, an optionally substituted aromatic acyl group, anoptionally substituted alkoxycarbonyl group or a substituted methylenegroup which forms a Schiff base.

In the case of an allyloxycarbonyl group, it is particularly convenientto employ a method of removal using palladium and triphenylphosphine ornickel-tetracarbonyl, as the removal can be carried out with fewby-products.

When the amino-protecting group is an optionally substituted alkylgroup, optionally substituted alkenyl group or optionally substitutedsulfonyl group, usually the removal may be accomplished by treatmentwith an acid or base, under the same conditions as removal reaction whenthe amino-protecting group is an aliphatic acyl group, an aromatic acylgroup, an alkoxycarbonyl group or a substituted methylene group whichforms a Schiff base.

When the hydroxyl-protecting group is, for example, an optionallysubstituted silyl group such as trimethylsilyl, triethylsilyl,triisopropylsilyl, t-butyldimethylsilyl or t-butyldiphenylsilyl, it willusually be removed by treatment with a fluoride anion-generatingcompound such as tetrabutylammonium fluoride, hydrofluoric acid,hydrofluoric acid-pyridine or potassium fluoride, or with an inorganicacid such as hydrochloric acid, hydrobromic acid, sulfuric acid,perchloric acid or phosphoric acid, or an organic acid such as aceticacid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonicacid, camphor sulfonic acid, trifluoroacetic acid ortrifluoromethanesulfonic acid.

For removal with fluoride anion, an organic acid such as formic acid,acetic acid or propionic acid may be added to accelerate the reaction.

The inert solvent used for the reaction is not particularly restrictedso long as it is inert to the reaction, but it is preferably an ethersuch as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,dimethoxyethane or diethyleneglycol dimethyl ether; a nitrile such asacetonitrile or isobutyronitrile; an organic acid such as acetic acid;water; or a mixture of these solvents.

The reaction temperature and the reaction time will differ depending onthe starting compounds, catalyst and inert solvent used, but ordinarilythe reaction temperature will be between 0° C. and 100° C. (preferablybetween 10° C. and 50° C.), and the reaction time will be 1 to 24 hours.

When the hydroxyl-protecting group is an optionally substituted aralkylgroup or an optionally substituted aralkyloxycarbonyl group, a method ofcontact with a reducing agent in an inert solvent (preferably catalyticreduction at ordinary temperature in the presence of a catalyst) or amethod of removal using an oxidizing agent is generally preferred.

The inert solvent used for removal by catalytic reduction is notparticularly restricted so long as it does not participate in thereaction, and as examples there may be mentioned aliphatic hydrocarbonssuch as hexane, heptane, ligroin and petroleum ether; aromatichydrocarbons such as toluene, benzene and xylene; esters such as ethylacetate and propyl acetate; ethers such as diethyl ether, diisopropylether, tetrahydrofuran, dioxane, dimethoxyethane and diethyleneglycoldimethyl ether; alcohols such as methanol, ethanol, n-propanol,isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol,diethylene glycol, glycerin, octanol, cyclohexanol and methylcellosolve;amides such as formamide, dimethylformamide, dimethylacetamide,N-methyl-2-pyrrolidone and hexamethylphosphoric triamide; aliphaticacids such as formic acid and acetic acid; water; and mixtures of thesesolvents, among which alcohols (most preferably methanol and ethanol)are preferred.

There are no particular restrictions on the catalyst used for removal bycatalytic reduction so long as it is one commonly used for removal ofthe hydroxyl-protecting group by catalytic reduction, and as examplesthere may be mentioned palladium-carbon, palladium black, Raney nickel,platinum oxide, platinum black, rhodium-aluminum oxide,triphenylphosphine-rhodium chloride or palladium-barium sulfate, amongwhich palladium-carbon is preferred.

There are no particular restrictions on the pressure, but it willordinarily be from 1 to 10 atmospheres.

The reaction temperature and the reaction time will differ depending onthe starting compounds, catalyst and insert solvent, but usually thereaction temperature will be between 0° C. and 100° C. (preferablybetween 20° C. and 70° C.), and the reaction time will be between 5minutes and 48 hours (preferably between 1 hour and 24 hours).

The inert solvent used for removal by oxidation is not particularlyrestricted so long as it does not participate in the reaction, but it ispreferably a water-containing solvent, and there may be mentioned asexamples ketones such as acetone; halogenated hydrocarbons such asmethylene chloride, chloroform and carbon tetrachloride; nitriles suchas acetonitrile; ethers such as diethyl ether, tetrahydrofuran anddioxane; amides such as dimethylformamide, dimethylacetamide andhexamethylphosphoric triamide; and sulfoxides such as dimethylsulfoxide.

The oxidizing agent used for this reaction is not particularlyrestricted so long as it is an oxidizing agent used for removal of thehydroxyl-protecting group, but it is preferably potassium persulfate,sodium persulfate, ammonium cerium nitrate (CAN) or2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ).

The reaction temperature and the reaction time will differ depending onthe starting compounds, oxidizing agent and inert solvent, but usuallythe reaction temperature will be between 0° C. and 150° C., and thereaction time will be between 10 minutes and 24 hours.

The removal can also be accomplished by reaction with an alkali metalsuch as lithium metal or sodium metal in liquid ammonia or an alcoholsuch as methanol, ethanol, n-propanol, isopropanol, n-butanol,isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin,octanol, cyclohexanol or methylcellosolve, at a temperature of between−78° C. and 0° C.

The removal can also be accomplished using aluminum chloride-sodiumiodide or an alkylsilyl iodide such as trimethylsilyl iodide, in aninert solvent.

The inert solvent used in this reaction is not particularly restrictedso long as it does not participate in the reaction, but it is preferablya halogenated hydrocarbon such as methylene chloride, chloroform orcarbon tetrachloride; a nitrile such as acetonitrile; or a mixture ofthese solvents.

The reaction temperature and the reaction time will differ depending onthe starting compounds and the inert solvent, but usually the reactiontemperature will be between 0° C. and 50° C., and the reaction time willbe between 5 minutes and 72 hours.

When the hydroxyl-protecting group is an aliphatic acyl group, anaromatic acyl group or an optionally substituted alkoxycarbonyl group,it may be removed by treatment with a base in an inert solvent.

There are no particular restrictions on the base used for this reactionso long as it is a base ordinarily used for removal of thehydroxyl-protecting group, and for example, it may be an alkali metalcarbonic acid salt such as lithium carbonate, sodium carbonate orpotassium carbonate; an alkali hydrogencarbonate such as lithiumhydrogencarbonate, sodium hydrogencarbonate or potassiumhydrogencarbonate; an alkali metal hydroxide such as lithium hydroxide,sodium hydroxide or potassium hydroxide; a metal alkoxide such aslithium methoxide, sodium methoxide, sodium ethoxide orpotassium-t-butoxide; or an ammonia mixture such as aqueous ammonia orconcentrated ammonia-methanol, among which alkali metal hydroxides,metal alkoxides and ammonia mixtures (most preferably alkali metalhydroxides and metal alkoxides) are preferred.

The inert solvent used for this reaction is not particularly restrictedso long as it is ordinarily used for hydrolysis reaction, but it ispreferably an ether such as diethyl ether, diisopropyl ether,tetrahydrofuran, dioxane, dimethoxyethane or diethyleneglycol dimethylether; an alcohol such as methanol, ethanol, n-propanol, isopropanol,n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol,glycerin, octanol, cyclohexanol or methylcellosolve; water; or a mixtureof these solvents.

The reaction temperature and the reaction time will differ depending onthe starting compounds and the base and inert solvent used, but in orderto inhibit by-products, the reaction temperature will usually be between−20° C. and 150° C., and the reaction time will usually be 1-10 hours.

When the hydroxyl-protecting group is optionally substitutedalkoxymethyl, optionally substituted alkylthiomethyl, tetrahydropyranyl,tetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl oroptionally substituted ethyl such as 1-ethoxyethyl, it will usually beremoved by treatment with an acid in an inert solvent.

There are no particular restrictions on the acid used for this reactionso long as it is an acid used for removal of the hydroxyl-protectinggroup, but usually compounds ordinarily used as Bronsted acids or Lewisacids may be mentioned, and preferred are Bronsted acids includinghydrogen chloride; inorganic acids such as hydrochloric acid, sulfuricacid and nitric acid; and organic acids such as acetic acid,trifluoroacetic acid, methanesulfonic acid and p-toluenesulfonic acid;or Lewis acids such as boron trifluoride, while strong acid cationexchange resins such as DOWEX 50W may also be used.

There are no particular restrictions on the inert solvent used for thisreaction so long as it is inert to the reaction, and for example, theremay be mentioned aliphatic hydrocarbons such as hexane, heptane, ligroinand petroleum ether; aromatic hydrocarbons such as benzene, toluene andxylene; halogenated hydrocarbons such as methylene chloride, chloroform,carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene;esters such as ethyl formate, ethyl acetate, propyl acetate, butylacetate and diethyl carbonate; ethers such as diethyl ether, diisopropylether, tetrahydrofuran, dioxane, dimethoxyethane and diethyleneglycoldimethyl ether; alcohols such as methanol, ethanol, n-propanol,isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol,diethylene glycol, glycerin, octanol, cyclohexanol and methylcellosolve;ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone,isophorone and cyclohexanone; water; and mixtures of these solvents,among which ethers and alcohols (most preferably tetrahydrofuran andmethanol) are preferred.

The reaction temperature and the reaction time will differ depending onthe starting compound and the acid and inert solvent used, but usuallythe reaction temperature will be between −10° C. and 200° C. (preferablybetween 0° C. and 150° C.), and the reaction time will be between 5minutes and 48 hours (preferably between 30 minutes and 10 hours).

When the hydroxyl-protecting group is an optionally substitutedalkenyloxycarbonyl group or optionally substituted sulfonyl group,usually the removal may be accomplished by treatment with a base, underthe same conditions as removal reaction when the hydroxyl-protectinggroup is the aforementioned optionally substituted aliphatic acyl group,optionally substituted aromatic acyl group or optionally substitutedalkoxycarbonyl group.

In the case of an allyloxycarbonyl group, it is particularly convenientto employ a method of removal using palladium and triphenylphosphine orbis(methyldiphenylphosphine)(1,5-cyclooctadiene)iridium(I)hexafluorophosphate, as the removal can be carried out with fewby-products.

When the carboxyl-protecting group is a lower alkyl group, a loweralkenyl group or a lower alkynyl group, or an optionally substitutedsilyl group, or when the compound has been converted to an ortho esterfor the purpose of protection, a method of removal by treatment with anacid or base, or using an enzyme, is preferred.

There are no particular restrictions on the acid used for this reactionso long as it is used for removal of the carboxyl-protecting group, andfor example, it may be hydrochloric acid, sulfuric acid, phosphoric acidor hydrobromic acid.

There are no particular restrictions on the base used for this reactionso long as it is used for removal of the carboxyl-protecting group, andfor example, it may be an alkali metal carbonate such as sodiumcarbonate or potassium carbonate; an alkali metal hydroxide such assodium hydroxide or potassium hydroxide; or concentratedammonia-methanol solution, among which sodium hydroxide is preferred.

Isomerization may occur with hydrolysis using a base.

There are no particular restrictions on the enzyme used for the reactionso long as it is an enzyme used for removal of the carboxyl-protectinggroup, and for example, it may be a lipase or an esterase.

The solvent used for this reaction may be, for example, water, analcohol such as methanol, ethanol or n-propanol; an ether such astetrahydrofuran or dioxane; or a mixture of any of these solvents withwater, among which an alcohol (most preferably methanol) is preferred.

The reaction temperature and the reaction time will differ depending onthe starting compounds, the solvent and the reagents used and are notparticularly restricted, but in order to inhibit by-products, thereaction temperature will usually be between 0° C. and 220° C., and thereaction time will usually be between 30 minutes and 10 hours.

When the carboxyl-protecting group is an optionally substituted aralkylgroup or halogeno lower alkyl group, it will usually be removed byreduction in a solvent.

The reduction method is preferably a method by chemical reduction withzinc-acetic acid when the carboxyl-protecting group is a halogeno loweralkyl group, and when it is an optionally substituted aralkyl group, themethod may be one of catalytic reduction using a catalyst such aspalladium-carbon or platinum, or a method of chemical reduction using analkali metal sulfide such as potassium sulfide or sodium sulfide.

The solvent used is not particularly restricted so long as it does notparticipate in the reaction, but there are preferred alcohols such asmethanol and ethanol; ethers such as tetrahydrofuran and dioxane;aliphatic acids such as acetic acid; and mixtures of these solvents withwater.

The reaction temperature and the reaction time will differ depending onthe starting compounds, the solvent and the reduction method, butusually the reaction temperature will be between 0° C. and approximatelyroom temperature and the reaction time will be between 5 minutes and 12hours.

If the carbonyl group has been protected by conversion to a cyclic oracyclic ketal formed using, for example, an alcohol such as methanol,isopropanol or diethylene glycol or a thiol such as methanethiol,ethanethiol or propanedithiol, an acid may be used for reconversion to acarbonyl group.

The acid used for this reaction is not particularly restricted so longas it is an acid ordinarily used for reconversion to a carbonyl groupfrom a cyclic or acyclic ketal formed for the purpose of protecting thecarbonyl group, and for example, it may be a Bronsted acid, e.g. aninorganic acid such as hydrochloric acid, hydrobromic acid, sulfuricacid, perchloric acid or phosphoric acid, or an organic acid such asacetic acid, formic acid, oxalic acid, methanesulfonic acid,p-toluenesulfonic acid, camphor sulfonic acid, trifluoroacetic acid ortrifluoromethanesulfonic acid; a Lewis acid such as zinc chloride, tintetrachloride, boron trichloride, boron trifluoride or boron tribromide;or an acidic ion exchange resin, among which inorganic acids and organicacids (most preferably hydrochloric acid and p-toluenesulfonic acid) arepreferred.

There are no particular restrictions on the inert solvent used for thefirst stage of the reaction so long as it is inert to the reaction, andas examples there may be mentioned aliphatic hydrocarbons such ashexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons suchas benzene, toluene and xylene; halogenated hydrocarbons such aschloroform, dichloromethane, 1,2-dichloroethane and carbontetrachloride; esters such as methyl acetate, ethyl acetate, propylacetate, butyl acetate and diethyl carbonate; ethers such as diethylether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane anddiethyleneglycol dimethyl ether; alcohols such as methanol, ethanol,n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamylalcohol, diethylene glycol, glycerin, octanol, cyclohexanol andmethylcellosolve; amides such as formamide, dimethylformamide,dimethylacetamide and hexamethylphosphoric triamide; water; and mixturesof these solvents, among which ethers, alcohols and water (mostpreferably acetone, tetrahydrofuran and water) are preferred.

The reaction temperature will differ depending on the starting compoundsand the acid and solvent used, but usually it will be between −20° C.and the boiling point (preferably between 0° C. and 100° C.).

The reaction time will differ depending on the starting compounds, theacid and inert solvent used and the reaction temperature, but usually itwill be between 5 minutes and 48 hours, (preferably between 10 minutesand 24 hours).

In the case of a cyclic or acyclic ketal formed using a thiol, it isparticularly convenient to employ a method of removal using a substancesuch as Raney nickel or silver nitrate.

In the case of conversion to a cyclic ketal using, for example, formalinor acetone as protection of a diol, an acid may be used for reconversionto the diol.

The acid used for this reaction is not particularly restricted so longas it is an acid ordinarily used for reconversion to a diol from acyclic or acyclic ketal formed for the purpose of protecting the diol,and for example, it may be a Bronsted acid, e.g. an inorganic acid suchas hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acidor phosphoric acid, or an organic acid such as acetic acid, formic acid,oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid or trifluoromethanesulfonic acid; aLewis acid such as zinc chloride, tin tetrachloride, boron trichloride,boron trifluoride or boron tribromide; or an acidic ion exchange resin,among which inorganic acids and organic acids (most preferablyhydrochloric acid and p-toluenesulfonic acid) are preferred.

There are no particular restrictions on the inert solvent used for thefirst stage of the reaction so long as it is inert to the reaction, andas examples there may be mentioned aliphatic hydrocarbons such ashexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons suchas benzene, toluene and xylene; halogenated hydrocarbons such aschloroform, dichloromethane, 1,2-dichloroethane and carbontetrachloride; esters such as methyl acetate, ethyl acetate, propylacetate, butyl acetate and diethyl carbonate; ethers such as diethylether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane anddiethyleneglycol dimethyl ether; alcohols such as methanol, ethanol,n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamylalcohol, diethylene glycol, glycerin, octanol, cyclohexanol andmethylcellosolve; amides such as formamide, dimethylformamide,dimethylacetamide and hexamethylphosphoric triamide; water; and mixturesof these solvents, among which ethers, alcohols and water (mostpreferably acetone, tetrahydrofuran and water) are preferred.

The reaction temperature will differ depending on the starting compoundsand the acid and solvent used, but usually it will be between −20° C.and the boiling point (preferably between 0° C. and 100° C.).

The reaction time will differ depending on the starting compounds, theacid and inert solvent used and the reaction temperature, but usually itwill be between 5 minutes and 48 hours (preferably between 10 minutesand 24 hours).

Removal of the protecting groups for amino, hydroxyl, carbonyl and/orcarboxyl groups, or a diol, may be carried out in an appropriate order,for the desired removal reaction.

After completion of the reactions of each of the methods and stepsdescribed above, the target compound of each step may be recovered fromthe reaction mixture according to conventional procedures.

For example, when the entire reaction mixture is a liquid, it may bereturned to room temperature if necessary, or cooled on ice, thenallowed to neutralization of an acid, an alkali, an oxidizing agent or areducing agent if necessary, and then water and an organic solvent suchas ethyl acetate which is immiscible with water and which does not reactwith the target compound may be added, and the layer containing thetarget compound is separated. Next, there may be added a solvent whichis immiscible with the resultant layer and which does not react with thetarget compound, and the layer containing the target compound may bewashed and separated. If the layer is an organic layer, it may be driedusing a desiccant such as anhydrous magnesium sulfate or anhydroussodium sulfate, the solvent may be distilled off to recover the targetcompound. If the layer is an aqueous layer, it may be electricallydesalted and then lyophilized to recover the target compound.

When the entire reaction mixture is a liquid, if possible the substancesother than the target compound (for example, solvents, reagents, etc.)may be simply distilled off at atmospheric pressure or under reducedpressure to recover the target compound.

When the target compound alone precipitates as a solid, or when theentire reaction mixture is a liquid and the target compound aloneprecipitates as a solid during the recovery procedure, the targetcompound may be first filtered by a filtration method and the filteredtarget compound washed with a suitable organic or inorganic solvent anddried to allow treatment of the mother liquor in the same manner as whenthe entire reaction mixture is a liquid, in order to recover the targetcompound.

When only the reagent or catalyst is present in solid form, or when theentire reaction mixture is a liquid and the reagent or catalyst aloneprecipitates as a solid during the recovery procedure, with the targetcompound dissolved in the solution, the reagent or catalyst may be firstfiltered by a filtration method and the filtered reagent or catalystwashed with a suitable organic or inorganic solvent, and then theobtained wash liquids combined as the mother liquor and the obtainedmixture treated in the same manner as when the entire reaction mixtureis a liquid, in order to recover the target compound.

Particularly when substances other than the target compound in thereaction mixture do not inhibit the reaction of the subsequent step, thereaction mixture may be used directly for the subsequent step withoutisolation of the target compound.

The purity of the target compound recovered by the method describedabove may be improved by appropriately employing a recrystallizationmethod, chromatography method or distillation method.

When the recovered target compound is a solid, it will usually bepossible to improve the purity of the target compound byrecrystallization. For recrystallization, a single solvent or multiplesolvents which do not react with the target compound may be used.Specifically, the target compound is first dissolved in the single ormultiple solvents which do not react therewith, either at roomtemperature or with heating. The resulting solution is either cooled onice or allowed to stand at room temperature to crystallization of thetarget compound from the mixture.

When the recovered target compound is a liquid or a solid, the purity ofthe target compound may be improved by any of various chromatographymethods. A weak acid silica gel such as Silica Gel 60 (340-400 mesh) byMerck Co. or BW-300 (300 mesh) by Fuji Silysia Chemical Ltd. may be usedin most cases. When the target compound is basic and adsorption is toostrong on the aforementioned silica gels, Propylamine Coating Silica Gel(200-300 mesh) by Fuji Silysia Chemical Ltd. or the like may be used.When the target compound is dipolar or must be eluted with a polarsolvent such as methanol, NAM-200H or NAM-300H by Nam Research Co. maybe used. These silica gels may be used for elution of the targetcompound with a single solvent or multiple solvents which do not reactwith the target compound, followed by distilling off of the solvent, toyield the target compound with improved purity.

When the recovered target compound is a liquid, its purity may beimproved by a distillation method. For distillation, the target compoundis subjected to reduced pressure at room temperature or with heating todistill off the target compound.

Representative examples of production methods for compounds (1) and(100) according to the present invention have been described above, butthe starting compounds and reagents used for production of the compoundsof the invention may also form salts, hydrates or solvates, which willdiffer depending on the starting materials and solvents used, and arenot particularly restricted so long as they do not inhibit the reaction.The solvents used will also differ depending on the starting materialsand reagents, but of course they are not particularly restricted so longas they dissolve the starting materials to some extent and do notinhibit the reaction. When compounds (1) and (100) of the invention areobtained in the free form, a conventional procedure may be carried outto convert it to a salt or hydrate which compounds (1) and (100) mayform.

When compounds (1) and (100) of the invention are obtained as a salt ofcompounds (1) and (100) or a hydrate of compounds (1) and (100), it maybe converted to the free form of compounds (1) and (100) according to aconventional procedure.

Also, the various isomers obtained for compounds (1) and (100) accordingto the invention (for example, geometric isomers, optical isomers basedon asymmetric carbons, rotational isomers, stereoisomers and tautomers,etc.) may be purified and isolated using ordinary separation means suchas recrystallization, diastereomer salt methods, enzyme fractionationmethods, and various chromatography (for example, thin-layerchromatography, column chromatography, gas chromatography and the like).

The starting compounds for Method A, Method B, Method C, Method D,Method E, Method F, Method G, Method H, Method K, Method M, Method N,Method P, Method Q, Method R, Method S, Method T, Method U and Method Vdescribed above may be commercially available compounds, or they may beeasily produced from commercially available compounds by methods whichare well known in the field. They may also be produced by the followingmethods.

Production Method for Compound (2A) (Method 1-1)

This method is a method of producing compound (2A) (the compound (2)above wherein X1 is nitrogen) by reacting compound (28) with compound(9) (amination or amidation) in an inert solvent, in the presence of apalladium(0) catalyst or copper catalyst, in the presence or in theabsence of a base, in the presence or in the absence of an additive,under or not under an inert gas atmosphere, and then removing theprotecting group Pro 1.

In this scheme, n, W1a, R10a, R20a, R21a, R22a, R23a, R30a, R31a andR32a have the same definitions as above. Also, Pro1 is anamino-protecting group, and for example, it may be an optionallysubstituted silyl group such as trimethylsilyl, triethylsilyl ort-butyldiphenylsilyl, an optionally substituted aliphatic acyl groupsuch as formyl or acetyl, an optionally substituted aromatic acyl groupsuch as benzoyl, an optionally substituted alkoxycarbonyl group such asethoxycarbonyl or t-butoxycarbonyl, a substituted methylene group whichforms a Schiff base, an optionally substituted aralkyl group such asbenzyl, 4-methoxybenzyl or 4-nitrobenzyl, an optionally substitutedaralkyloxycarbonyl group such as benzyloxycarbonyl,4-methoxybenzyloxycarbonyl or 4-nitrobenzyloxycarbonyl, an optionallysubstituted alkenyloxycarbonyl group such as vinyloxycarbonyl orallyloxycarbonyl, an optionally substituted alkyl group, an optionallysubstituted alkenyl group or an optionally substituted sulfonyl group,preferably a lower alkoxycarbonyl group such as methoxycarbonyl,ethoxycarbonyl, t-butoxycarbonyl or isobutoxycarbonyl, a loweralkoxycarbonyl group substituted with a halogen or tri lower alkylsilyl, such as 2,2,2-trichloroethoxycarbonyl or2-trimethylsilylethoxycarbonyl, an alkenyloxycarbonyl group such asvinyloxycarbonyl or allyloxycarbonyl, an optionally substitutedaralkyloxycarbonyl group such as benzyloxycarbonyl,4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl,2-nitrobenzyloxycarbonyl or 4-nitrobenzyloxycarbonyl, or an optionallysubstituted aralkyl group such as benzyl, 4-methoxybenzyl,3,4-dimethoxybenzyl, 2-nitrobenzyl or 4-nitrobenzyl, and more preferablybenzyl, 4-methoxybenzyl, 4-nitrobenzyl, ethoxycarbonyl, t-butoxycarbonylor benzyloxycarbonyl.

The method may be carried out in a manner similar to Method F describedabove.

Production Method for Compound (2A) (Method 1-2)

This method is a method of producing compound (2A) (the compound (2)above wherein X1 is nitrogen) by reacting compound (29) with compound(12) in an inert solvent or without a solvent, under or not under aninert gas atmosphere, in the presence or in the absence of a base, inthe presence or in the absence of an additive to yield compound (2A),and afterwards removing the protecting group Pro1.

In this scheme, n, W1, R10a, R20a, R21a, R22a, R23a, R30a, R31a and R32ahave the same definitions as above.

HPro1 is hydrogen or has the same definition as group Pro1 above.

This method may be carried out in a manner similar to Method H describedabove.

Production Method for Compound (2C) (Method 1-3)

This method is a method of producing compound (2C) (the compound (2)above wherein R10 is R10b) by reacting compound (30) with compound (14)in an inert solvent, in the presence of a palladium(0) catalyst, underor not under an inert gas atmosphere, in the presence or in the absenceof a base, in the presence or in the absence of an additive, and thenremoving the protecting group Pro 1.

In this scheme, X1, n, W1a, M1b, Pro1, R10b, R20a, R21a, R22a, R23a,R30a, R31a and R32a have the same definitions as above.

This method may be carried out in a manner similar to Method K describedabove.

Production Method for Compound (2C) (Method 1-4)

This method is a method of producing compound (2c) (the compound (2)above wherein R10 is R10b) by reacting compound (31) with compound (16)in an inert solvent, in the presence of a palladium(0) catalyst, underor not under an inert gas atmosphere, in the presence or in the absenceof a base, in the presence or in the absence of an additive, and thenremoving the protecting group Pro1.

In this scheme, X1, n, W1a, M1, Pro1, R10b, R20a, R21a, R22a, R23a,R30a, R31a and R32a have the same definitions as above.

This method may be carried out in a manner similar to Method K describedabove.

Production Method for Compound (2A) (Method 1-5)

This method is a method of producing compound (2A) (the compound (2)above wherein X1 is nitrogen) by reacting compound (19) and compound(33) in an inert solvent, in the presence of a reducing agent, in thepresence or in the absence of an acid, in the presence or in the absenceof an additive, to yield compound (2A), and afterward removing theprotecting group Pro1a by the method described above.

In this scheme, n, W1, E1, E2, E3, R10a, R20a, R21a, R22a, R23a, R30a,R31a and R32a have the same definitions as above.

Also, HPro1a is hydrogen or a group represented by Pro1a below.

Group Pro1a is an optionally substituted aralkyl group such as benzyl,4-methoxybenzyl, 3,4-dimethoxybenzyl, 2-nitrobenzyl or 4-nitrobenzyl,and is preferably benzyl.

This method may be carried out in a manner similar to Method C describedabove.

Production Method for Compound (2A) (Method 1-6)

This method is a method of producing compound (2A) (the compound (2)above wherein X1 is nitrogen) by reacting a base with compound (34) inan inert solvent, and then removing the protecting group Pro1 by themethod described above.

In this scheme, n, W1, Pro1, E4, E5, E6, R10a, R20a, R21a, R22a, R23a,R30a, R31a and R32a have the same definitions as above.

This method may be carried out in a manner similar to Method A describedabove.

Production Method for Compounds (2B) and (200) (Method 1-7)

This method is a method of producing compound (2B) (the compound (2)above wherein X1 is CH) by reacting compound (35) with compound (9) inan inert solvent, in the presence of a palladium(0) catalyst, subjectingit to hydrogenation reaction, and then removing the protecting groupPro1 (Method 1-7-1), or a method of producing compound (200) by reactingcompound (35) with compound (9) in the same manner, then removing theprotecting group Pro1 (Method 1-7-2).

In this scheme, n, W1a, M1, Pro1, R10a, R20a, R21a, R22a, R23a, R30a,R31a and R32a have the same definitions as above.

This method may be carried out in a manner similar to Method K describedabove, followed by hydrogenation reaction in a manner similar to MethodA above.

Production Method for Compounds (2B) and (200C) (Method 1-8)

This method is a method of producing compound (2B) (the compound (2)above wherein X1 is CH) by reacting compound (36) with compound (25) inan inert solvent, in the presence of a palladium(0) catalyst, subjectingit to hydrogenation reaction, and then removing the protecting groupPro1 (Method 1-8-1), or a method of producing compound (200C) (thecompound (200) above wherein R10 is R10b) by reacting compound (36) withcompound (25) in the same manner, then removing the protecting groupPro1 (Method 1-8-2).

In this scheme, n, W1a, M1, Pro1, R10a, R10b, R20a, R21a, R22a, R23a,R30a, R31a and R32a have the same definitions as above.

This method may be carried out in a manner similar to Method K describedabove, followed by hydrogenation reaction in a manner similar to MethodA above.

Production Method for Compounds (2B) and (200C) (Method 1-9)

This method is a method of producing compound (2B) (the compound (2)above wherein X1 is CH) by reacting compound (37) with compound (27)(i.e., a lithium reagent or Grignard reagent) in an inert solvent, inthe presence of an inert gas to yield an adduct (160) (Step 1-9-1), andthen reducing hydroxyl at the benzyl position of the resultant adduct(160) (Step 1-9-2), and removing the protecting group Pro1, or a methodof producing compound (200C) (the compound (200) above wherein R10 isR10b) by reacting in the same manner to yield an adduct (160) (Step1-9-1), then dehydrating hydroxyl at the benzyl position of theresultant adduct (160) in the presence of or in the absence of acid(Step 1-9-3), and further removing the protecting group Pro 1.

In this scheme, n, M2, Pro1, R10a, R10b, R20a, R21a, R22a, R23a, R30a,R31a and R32a have the same definitions as above.

This method may be carried out in a manner similar to Method U describedabove.

Production Method for Compound (19) (Method 2)

This method is a method of producing compound (19) by reacting anN-alkylating agent with compound (12) in an inert solvent to yieldcompound (38) (Step 2-1), and then reacting an N-alkylating agent orN-carbonylating agent with compound (38) to yield compound (39) (Step2-2), and reacting an oxidizing agent with compound (39) in the presenceor in the absence of an additive (Step 2-3).

In this scheme, W1, E1, E2, E3, R10a, R20a, R21a, R22a and R23a have thesame definitions as above. Also, E7 is a group suitable for obtainingthe desired group of the formula E2(CO)E1-.

Step 2-1 and Step 2-2 may be carried out in a manner similar to Method Adescribed above.

(Step 2-3)

There are no particular restrictions on the solvent used so long as itdissolves the starting compound to some extent and does not inhibit thereaction of this step, and specifically there may be mentionedhalogenated hydrocarbons such as chloroform, dichloromethane,1,2-dichloroethane and carbon tetrachloride, and nitrites such asacetonitrile and isobutyronitrile, among which halogenated hydrocarbons(particularly dichloromethane) are preferred.

There are no particular restrictions on the oxidizing agent used so longas it can yield the target compound and does not produce any unseparableby-products, and specifically there may be mentioned chromic acids suchas pyridinium chlorochromate (PCC) and pyridinium dichromate (PDC),Dess-Martin reagent (Dess D. B., Martin J. C., J. Am. Chem. Soc.,(1991), 113, 7277), or catalytic amounts of dimethylsulfoxide oxidizingagents such as tetrapropylammonium perruthenate (VII) (TPAP; Ley S. V.et al., Synthesis, (1994), 639) and dimethylsulfoxide-oxalyl chloride(Swern oxidizing agent; D. Swern et al., Synthesis, (1981), 165), in thepresence of N-methylmorpholine-N-oxide (NMO) as an auxiliary oxidizingagent, among which dimethylsulfoxide-oxalyl chloride (Swern oxidizingagent) is preferred.

There are no particular restrictions on the additive used so long as itcan yield the target compound and does not produce any unseparableby-products, and specifically there may be mentioned Celite andmolecular sieve, among which molecular sieve is preferred.

The reaction temperature will differ depending on the startingmaterials, solvent and reagents, but will usually be between −80° C. and60° C., and is preferably between −80° C. and 40° C.

The reaction time will differ depending on the starting materials,solvent, reagents and reaction temperature, but will usually be 0.1 to100 hours, and is preferably 1 to 12 hours.

Compound (38), compound (39) or compound (19) may be isolated orpurified from the reaction mixtures obtained above by the methodsdescribed above.

Production Method for Compound (21) and compound (34) (Method 3)

This method is a method of producing compound (21) or compound (34) byreacting an N-alkylating agent or N-carbonylating agent with compound(40) in an inert solvent to yield compound (41) (Step 3-1), and thenoxidizing compound (41) to yield compound (42) (Step 3-2), and reactingcompound (42) with compound (12) (Step 3-3).

In this scheme, W1, E4, E5, E6, R10a, R20a, R21a, R22a and R23a have thesame definitions as above. Also, E8 is a group suitable for obtainingthe desired group of the formula E4(CO)E5. PR40a has the same definitionas R40a above, or is an amino-protecting group (preferablyt-butoxycarbonyl or benzyl).

Step 3-1 in this method may be carried out in a manner similar to MethodA above, Step 3-2 may be carried out in a manner similar to Method 2above (Step 2-3), and Step 3-3 may be carried out in a manner similar toMethod C above.

Production Method for Compound (24A), Compound (36A), Compound (22),Compound (35), Compound (24B) and Compound (36B) (Method 4)

This method is a method of introducing a trifluoromethanesulfonyl groupinto compound (43) in an inert solvent under an inert gas atmosphere toyield compound (24A) or compound (36A) (Step 4-1), and then reactingcompound (24A) or compound (36A) with boron metal reagent or tin metalreagent in the presence of a palladium(0) catalyst to yield compound(22) or compound (35) (Step 4-2), and reacting compound (22) or compound(35) with a halogenating reagent, in the presence or in the absence of abase, to yield compound (24B) or compound (36B) (Step 4-3). Compound(43) may also be directly reacted with a halogenating agent to producecompound (24B) or compound (36B) (Step 4-4).

In this scheme, n, R30a, R31a, R32a and PR40a have the same definitionsas above.

Also, Hal represents chlorine, bromine or iodine.

M1b is a group of the formula B(OE^(10c))₂ or Sn(E^(10b))₃ (whereinE^(10c) represents C1-6 alkyl or the two of E^(10c) bond together toform C2-3 alkylene optionally substituted with methyl, and E^(10b)represents C1-6 alkyl).

Tf is trifluoromethanesulfonyl.

(Step 4-1)

There are no particular restrictions on the solvent used so long as itdissolves the starting compound to some extent and does not inhibit thereaction of this step, and specifically there may be mentioned etherssuch as diethyl ether, tetrahydrofuran and dioxane, among whichtetrahydrofuran is preferred.

This step is preferably carried out under a dried inert gas atmosphere.The inert gas is preferably argon or nitrogen.

There are no particular restrictions on the base used so long as it canyield the target compound and does not produce any unseparableby-products, and specifically there may be mentioned alkali metal amidessuch as lithium bis(trimethylsilyl)amide, sodiumbis(trimethylsilyl)amide and lithium diisopropylamide, among whichlithium bis(trimethylsilyl)amide or lithium (diisopropylamide) ispreferred.

There are no particular restrictions on thetrifluoromethanesulfonylating reagent used so long as it can yield thetarget compound and does not produce any unseparable by-products, but itis preferably N-phenyl bis(trifluoromethanesulfonimide).

The reaction temperature for enolation will differ depending on thestarting materials, solvent and reagents, but will usually be between−100 and 20° C., and is preferably between −80 and −30° C.

The reaction temperature for conversion to a leaving group will differdepending on the starting materials, solvent and reagents, but willusually be between −100° C. and 50° C., and is preferably between −80°C. and 30° C.

The reaction time for enolation will differ depending on the startingmaterials, solvent, reagents and reaction temperature, but will usuallybe 0.1 to 5 hours, and is preferably 0.1 to 3 hours.

The reaction time for conversion to a leaving group will differdepending on the starting materials, solvent, reagents and reactiontemperature, but will usually be 0.1 to 24 hours, and is preferably 0.5to 12 hours.

In addition to the method described above, compound (44) may be producedby reacting a ketone compound (43) with trifluoromethanesulfonicanhydride in an inert solvent such as dichloromethane, in the presenceof an organic base such as 2,6-di-t-butyl-4-methylpyridine, as describedin David Crich et al., Synthesis, (2001), 2, 323, for example.

(Step 4-2)

(Production Method for Compound (22) and Compound (35) as BoronateDerivatives)

There are no particular restrictions on the solvent used so long as itdissolves the starting compound to some extent and does not inhibit thereaction of this step, and specifically there may be mentioned amidessuch as formamide, dimethylformamide, dimethylacetamide andhexamethylphosphoric triamide; or sulfoxides such as dimethylsulfoxideand sulfolane, ethers such as diethyl ether, diisopropyl ether,tetrahydrofuran, dioxane, dimethoxyethane and diethyleneglycol dimethylether, and aromatic hydrocarbons such as benzene, toluene and xylene,among which dimethylsulfoxide and dioxane are preferred.

There are no particular restrictions on the metal catalyst used so longas it can yield the target compound and does not produce any unseparableby-products, and specifically there may be mentioned divalent palladiumcompounds such as[1,1′-bis(diphenylphosphino)triphenylphosphine]palladium(II) chlorideand 0-valent palladium compounds such astetrakis(triphenylphosphine)palladium, among which[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) ispreferred.

As bases to be used there may be mentioned potassium phenoxide,triethylamine, potassium phosphate, potassium carbonate and potassiumacetates, among which potassium acetate is preferred.

The catalyst used may be triphenylarsine.

The reaction temperature will differ depending on the startingmaterials, solvent and reagents, but will usually be between 50° C. and80° C.

The reaction time will differ depending on the starting materials,solvent, reagents and reaction temperature, but will usually be 1 to 6hours, and is preferably 2 to 3 hours.

(Production Method for Compound (22) and compound (35) as tinderivatives)

There are no particular restrictions on the solvent used so long as itdissolves the starting compound to some extent and does not inhibit thereaction of this step, and specifically there may be mentioned amidessuch as formamide, dimethylformamide, dimethylacetamide andhexamethylphosphoric triamide, and ethers such as diethyl ether,diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane anddiethyleneglycol dimethyl ether, among which ethers (particularlytetrahydrofuran) are preferred.

There are no particular restrictions on the metal catalyst used so longas it can yield the target compound and does not produce any unseparableby-products, and specifically there may be mentioned 0-valent palladiumcompounds such as tetrakis(triphenylphosphine)palladium(0) andtris(dibenzylideneacetone)dipalladium(0).

As tin reagents to be used there may be mentioned hexamethylditin(IV),hexabutylditin(IV) and hexaphenylditin(IV), among whichhexamethylditin(IV) is preferred.

The reaction temperature will differ depending on the startingmaterials, solvent and reagents, but will usually be between −70° C. and80° C., and is preferably between 50° C. and 80° C.

The reaction time will differ depending on the starting materials,solvent, reagents and reaction temperature, but will usually be 1 to 8hours, and is preferably 2 to 4 hours.

As supplementary literature to be used as reference for carrying outthis method, there may be mentioned Kurt Ritter et al., Synthesis 1993;735-762.

(Step 4-3)

There are no particular restrictions on the solvent used so long as itdissolves the starting compound to some extent and does not inhibit thereaction of this step, and specifically there may be mentionedhalogenated hydrocarbons such as chloroform, dichloromethane,1,2-dichloroethane and carbon tetrachloride, and ethers such as diethylether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane anddiethyleneglycol dimethyl ether, among which dichloromethane, carbontetrachloride, diethyl ether and tetrahydrofuran are preferred.

There are no particular restrictions on the halogenating reagent used solong as it can yield the target compound and does not produce anyunseparable by-products, and specifically there may be mentionedchlorine, bromine, iodine, N-chlorosuccinimide, N-bromosuccinimide,N-iodosuccinimide and copper chloride, among which chlorine, bromine andiodine are preferred.

When a base is used, there may be mentioned sodium hydroxide, pyridineand sodium methoxide.

The reaction temperature will differ depending on the startingmaterials, solvent and reagents, but will usually be between −78° C. and25° C., and is preferably between 0° C. and 25° C.

The reaction time will differ depending on the starting materials,solvent, reagents and reaction temperature, but will usually be 1 to 24hours, and is preferably 1 to 6 hours.

(Step 4-4)

There are no particular restrictions on the solvent used so long as itdissolves the starting compounds to some extent and does not inhibit thereaction of this step, and specifically there may be mentionedhalogenated hydrocarbons such as chloroform, dichloromethane,1,2-dichloroethane and carbon tetrachloride, and aromatic hydrocarbonssuch as benzene, toluene and xylene, among which chloroform,dichloromethane and carbon tetrachloride are preferred.

There are no particular restrictions on the halogenating agent used solong as it can yield the target compound and does not produce anyunseparable by-products, and specifically there may be mentionedhalogenating agents such as chlorine, oxalic chloride, thionyl chloride,phosphorus oxychloride, phosphorus trichloride, phosphoruspentachloride, bromine, oxalic bromide, thionyl bromide, phosphorustribromide, 2,2,2-tribromo-1,3,2-benzodioxaphosphol, iodine andphosphorus triiodide, among which phosphorus trichloride, phosphorustribromide, 2,2,2-tribromo-1,3,2-benzodioxaphosphol and phosphorustriiodide are preferred.

The reaction temperature will differ depending on the startingmaterials, solvent and reagents, but will usually be between 0° C. and70° C.

The reaction time will differ depending on the starting materials,solvent, reagents and reaction temperature, but will usually be 1 to 24hours.

Production Method for Compound (25), Compound (27) and Compound (9A)(Method 5)

In this method, compound (45) is reacted with compound (14) in an inertsolvent in the presence of a palladium(0) catalyst to yield compound(9A) (Step 5-1), and then compound (9A) is reacted with a lithiatingagent or Grignard reagent-producing agent to yield compound (27) (Step5-2) and compound (27) is reacted with a boron metal reagent or tinmetal reagent to produce compound (25) (Step 5-3).

In this scheme, M1, M1b, M2, R10b, R20a, R21a, R22a and R23a have thesame definitions as above.

Hal1 is chlorine or bromine, and Hal2 is iodine when Hal1 is bromine,and bromine or iodine when Hal1 is chlorine.

Step 5-1 of this method may be carried out in a manner similar to MethodK above.

(Step 5-2)

This step will differ depending on the nature of M2.

(Grignard Reagent Production Step)

In this step, compound (9A) is directly reacted with magnesium metal inan inert solvent (direct method), or magnesium-halogen exchange reactionis carried out between compound (9A) and another Grignard reagent(indirect method) to produce compound (27) (i.e., a Grignard reagent).

(1) Direct Method

There are no particular restrictions on the solvent used so long as itdissolves the starting compound to some extent and does not inhibit thereaction of this step, and specifically there may be mentioned etherssuch as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,dimethoxyethane and diethyleneglycol dimethyl ether, and phosphoricamides such as hexamethylphosphoric triamide, among which ethers(particularly diethyl ether and tetrahydrofuran) are preferred.

The reaction method may be conducted according to a common procedure,and specifically magnesium metal is suspended in the solvent under anatmosphere of an inert gas such as nitrogen or argon, in the presence orin the absence of a catalytic amount of iodine or dibromoethane as anactivating agent, and compound (9A) is slowly added to the reactionsystem. Upon completion of the reaction, compound (27) is produced inthe supernatant, and it is usually used for the next step withoutisolation.

The reaction temperature will differ depending on the startingmaterials, solvent and reagents, but will usually be between −20° C. and150° C., and is preferably between 0° C. and 100° C.

The reaction time will differ depending on the starting materials,solvent, reagents and reaction temperature, but will usually be 1 to 10hours.

(2) Indirect Method

The solvent used, the reaction temperature and the reaction time are thesame as for the direct method.

The reaction method may be carried out according to a common procedure,but compound (27) (i.e. an organic magnesium compound) may also beproduced by reacting the halogen compound (9A) with isopropylmagnesiumbromide or the like under an atmosphere of an inert gas such as nitrogenor argon. The resultant compound (27) is usually used for the next stepwithout isolation.

(Lithiating Step)

In this step, lithium-halogen exchange reaction is carried out betweenthe halogen compound (9A) and another alkyllithium reagent in an inertsolvent, under an atmosphere of an inert gas such as nitrogen or argon,to produce an arylithium reagent (27).

There are no particular restrictions on the solvent used so long as itdissolves the starting compound to some extent and does not inhibit thereaction of this step, and specifically there may be mentioned etherssuch as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,dimethoxyethane and diethyleneglycol dimethyl ether, and phosphoricamides such as hexamethylphosphoric triamide, among which ethers(particularly diethyl ether and tetrahydrofuran) are preferred.

There are no particular restrictions on the alkyllithium reagent used solong as it can yield the target compound and does not produce anyunseparable by-products, and specifically there may be mentionedalkyllithium compounds such as n-butyllithium, sec-butyllithium andt-butyllithium, among which n-butyllithium is preferred.

The reaction temperature will differ depending on the startingmaterials, solvent and reagents, but will usually be between −100° C.and 0° C.

The reaction time will differ depending on the starting materials,solvent, reagents and reaction temperature, but will usually be between10 minutes and 2 hours.

The resultant compound (27) is usually used for the next step withoutisolation.

(Step 5-3)

This step will differ depending on the nature of M1.

(Step for the Production of a Boronic Acid Reagent)

In this step, the lithium agent or Grignard reagent (27) produced inStep 5-2 is reacted with a borate reagent mentioned below to produce aboronic acid reagent compound (25).

There are no particular restrictions on the solvent used so long as itdissolves the starting compound to some extent and does not inhibit thereaction of this step, and specifically there may be mentioned etherssuch as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,dimethoxyethane and diethyleneglycol dimethyl ether, and phosphoricamides such as hexamethylphosphoric triamide, among which ethers(particularly diethyl ether and tetrahydrofuran) are preferred.

There are no particular restrictions on the borate reagent used so longas it can yield the target compound and does not produce any unseparableby-products, and specifically there may be mentioned trialkylboratessuch as triisopropylborate and trimethylborate, among whichtriisopropylborate are preferred.

The trialkylborate obtained may be easily hydrolyzed in water or aqueousammonium chloride to produce a boronic acid reagent compound (25).

The reaction temperature will differ depending on the startingmaterials, solvent and reagents, but will usually be between −80° C. and50° C., and is preferably between −80° C. and 30° C.

The reaction time will differ depending on the starting materials,solvent, reagents and reaction temperature, but will usually be 1 to 10hours, and is preferably 2 to 6 hours.

(Step for the Production of a Tin Reagent)

In this step, the lithium agent or Grignard reagent (27) produced inStep 5-2 is reacted with the halogenated trialkyltin reagent mentionedbelow to produce a tin reagent compound (25).

There are no particular restrictions on the solvent used so long as itdissolves the starting compound to some extent and does not inhibit thereaction of this step, and specifically there may be mentioned etherssuch as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,dimethoxyethane and diethyleneglycol dimethyl ether, and phosphoricamides such as hexamethylphosphoric triamide, among which ethers(particularly diethyl ether and tetrahydrofuran) are preferred.

There are no particular restrictions on the halogenated trialkyltinreagent used so long as it can yield the target compound and does notproduce any unseparable by-products, and specifically there may bementioned halogenated trialkyltin compounds such as tributyltin chlorideand trimethyltin chloride, among which tributyltin chloride ispreferred.

The reaction temperature will differ depending on the startingmaterials, solvent and reagents, but will usually be between −80° C. and50° C., and is preferably between −80° C. and 30° C.

The reaction time will differ depending on the starting materials,solvent, reagents and reaction temperature, but will usually be 1 to 10hours, and is preferably 1 to 6 hours.

Production Method for Compound (9B) (Method 6)

In this step, compound (46) is reacted with compound (14) in an inertsolvent in the presence of a palladium(0) catalyst, to yield compound(47) (Step 6-1), and then compound (47) is reacted with a de-alkylatingagent or de-aralkylating agent to yield compound (48) (Step 6-2), and atrifluoromethanesulfonyl group is introduced at the phenolic hydroxylgroup of compound (48) to produce compound (9B) (Step 6-3).

In this scheme, Tf, M1b, Hal, R10a, R10b, R20a, R21a, R22a and R23a havethe same definitions as above. Also, R100 represents C1-6 alkyl oroptionally substituted aralkyl, and is preferably methyl or benzyl.

Step 6-1 of this method may be carried out in a manner similar to MethodK described above.

(Step 6-2)

There are no particular restrictions on the solvent used so long as itdissolves the starting compounds to some extent and does not inhibit thereaction of this step, and specifically there may be mentioned alcoholssuch as methanol, ethanol and isopropanol, ethers such as diethyl ether,diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane anddiethyleneglycol dimethyl ether, aromatic hydrocarbons such as benzene,toluene and xylene, organic acids such as carbon disulfide, acetic acidand hydrogen bromide in acetic acid solution, organic bases such asquinoline and pyridine, and water. These may be selected as appropriatefor the de-alkylating agent or de-aralkylating agent used.

There are no particular restrictions on the de-alkylating agent orde-aralkylating agent used so long as it can yield the target compoundand does not produce any unseparable by-products, and specifically theremay be mentioned Lewis acids such as boron tribromide, borontrichloride, boron triiodide and aluminum chloride, Bronsted acids suchas hydrobromic acid, hydrochloric acid and hydrogen bromide in aceticacid solution, metal salts such as lithium iodide, and halogenatedsilanes such as trimethylsilane iodide.

The reaction temperature will differ depending on the startingmaterials, solvent and reagents, but will usually be between −80° C. and250° C.

The reaction time will differ depending on the starting materials,solvent, reagents and reaction temperature, but will usually be 0.1 to100 hours.

When R100 is an optionally substituted aralkyl group, thede-aralkylating step may be carried out according to the hydrogenationmethod described above for Method A.

The conditions may be selected as suitable for the starting materials,in order to allow selective deprotection.

As supplementary literature to be used as reference for carrying outthis method, there may be mentioned M. Vivekananda Bhatt, Surendra U.Kulkarni et al., “Cleavage of Ethers” Synthesis (1983), 249 and T. W.Greene, (Protective Groups in Organic Synthesis), John Wiley & Sons: J.F. W. McOmis, (Protective Groups in Organic Chemistry), Plenum Press.

Step 6-3 may be carried out in a manner similar to Method A or Method Bdescribed above.

Production Method for Compound (25A) (Method 7)

In this method, compound (9C) is reacted with a boron metal reagent ortin metal reagent in an inert solvent in the presence of a palladium(0)catalyst, to produce compound (25A).

In this scheme, M1b, Hal, R10a, R20a, R21a, R22a and R23a have the samedefinitions as above.

This method may be carried out in a manner similar to Step 4-2 of Method4.

Production Method for Compound (13A) (Method 8)

In this method, compound (49) is reacted with compound (8) (amination oramidation), in an inert solvent in the presence of a palladium(0)catalyst or copper catalyst, in the presence or in the absence of abase, in the presence or in the absence of an additive, under or notunder an inert gas atmosphere, to yield compound (50) (Step 8-1), andthen compound (50) is reacted with a de-alkylating agent orde-aralkylating agent to yield compound (51) (Step 8-2), and atrifluoromethanesulfonyl group is introduced at the phenolic hydroxyl ofcompound (51) to produce compound (13A) (Step 8-3).

In this scheme, Tf, n, R20a, R21a, R22a, R23a, R30a, R31a, R32a, R40a,R100 have the same definitions as above. Also, MW1a has the samedefinition as M1a or W1a above.

Step 8-1 of this method may be carried out in a manner similar to MethodF or Method G described above, Step 8-2 may be carried out in a mannersimilar to Step 6-2 described above, and Step 8-3 may be carried out ina manner similar to Method A or Method B described above.

Production Method for Compound (15) and Compound (13B) (Method 9)

In this method, compound (77) is reacted with compound (8), in an inertsolvent, in the presence of a palladium(0) catalyst or copper catalyst,in the presence or in the absence of a base, in the presence or in theabsence of an additive, under or not under an inert gas atmosphere, toyield compound (13B) (Step 9-1), and then compound (13B) is reacted witha metal reagent to produce compound (15) (Step 9-2).

In this scheme, n, M1, R20a, R21a, R22a, R23a, R30a, R31a, R32a and R40ahave the same definitions as above.

Hal4 is chlorine or bromine, and Hal3 is iodine when Hal4 is bromine,and bromine or iodine when Hal4 is chlorine.

Step 9-1 of this method may be carried out in a manner similar to MethodF above, and Step 9-2 may be carried out in a manner similar to Step 5-2and Step 5-3, or Method 7, above.

Production Method for Compound (16A), Compound (14) and Compound (16B)(Method 10)

In this method, a leaving group is introduced into compound (53), in aninert solvent, under or not under inert gas atmosphere, to yieldcompound (16A) (Step 10-1), and then compound (16A) is reacted with aboron metal reagent or tin metal reagent in the presence of apalladium(0) catalyst to yield compound (14) (Step 10-2), and compound(14) is reacted with a halogenating reagent to produce compound (16B)(Step 10-3).

Alternatively, compound (53) is reacted directly with a halogenatingagent to produce compound (16B) (Step 10-4).

In this scheme, Tf, R10b, M1b and Hal have the same definitions asabove.

Also, R200 has the same definition as the substituents of SubstituentGroup A above, or represents the substituents, the substituents thereonbeing protected. u is an integer of 0, 1, 2,3, 4 or 5. k is an integerof 0,1,2,3, 4 or 5.

Step 10-1 of this method may be carried out in a manner similar toMethod 4-1 above, Step 10-2 may be carried out in a manner similar toStep 4-2 above, and Step 10-3 may be carried out in a manner similar toStep 4-3 above. Step 10-4 may be carried out in a manner similar to Step4-4 above.

Production Method for Compound (12) (Method 11)

In this step, compound (54) is reacted with a nitrating reagent to yieldcompound (55) (Step 11-1), and then a metal or metal salt is used in thepresence of an acid for reduction of compound (55) to produce compound(12) (Step 11-2).

In this scheme, R10a, R20a, R21a, R22a and R23a have the samedefinitions as above.

(Step 11-1)

There are no particular restrictions on the solvent used so long as itdissolves the starting compounds to some extent and does not inhibit thereaction of this step, and specifically there may be mentioned asulfuric acid and nitric acid mixture or an acetic acid and nitric acidmixture, where the nitric acid solvent reacts as a nitrating agent.

The reaction temperature will differ depending on the startingmaterials, solvent and reagents, but will usually be between −20° C. and150° C., and is preferably between 0° C. and 80° C.

The reaction time will differ depending on the starting materials,solvent, reagents and reaction temperature, but will usually be 0.5 to48 hours, and is preferably 1 to 12 hours.

(Step 11-2)

There are no particular restrictions on the solvent used so long as itdissolves the starting compounds to some extent and does not inhibit thereaction of this step, and specifically there may be mentioned water,alcohols such as methanol and ethanol, amides such as formamide,dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide,organic acids such as acetic acid, and mixtures of these solvents, amongwhich a mixed solvent of ethanol and water, a mixed solvent of ethanoldimethylformamide and water, or acetic acid is preferred.

There are no particular restrictions on the metal or metal salt used solong as it can yield the target compound and does not produce anyunseparable by-products, and specifically there may be mentioned metalssuch as iron powder, tin powder and zinc powder, and metal salts such astin(II) chloride, among which a metal (particularly iron powder) ispreferred.

There are no particular restrictions on the acid used so long as it canyield the target compound and does not produce any unseparableby-products, and specifically there may be mentioned organic acids suchas acetic acid, and inorganic acids such as hydrochloric acid andammonium chloride, among which ammonium chloride is preferred.

The equivalents of the metal or metal salt used will differ depending onthe starting materials, solvent and reagents, but will usually be aproportion of 2-15 and preferably 3-6, in terms of the molar ratio withrespect to the starting material.

The reaction temperature will differ depending on the startingmaterials, solvent and reagents, but will usually be between 0° C. and150° C., and is preferably between 0° C. and 100° C.

The reaction time will differ depending on the starting materials,solvent, reagents and reaction temperature, but will usually be 0.5 to48 hours, and is preferably 1 to 12 hours.

Compound (55) or compound (12) may be isolated or purified from thereaction mixture obtained above by the method described above.

Production Method for Compound (55A) (Method 12)

In this method, compound (56) is reacted with compound (16) describedabove to produce compound (55A) (Method 12-1), or compound (57) isreacted with compound (14) described above to produce compound (55A)(Method 12-2), in an inert solvent, in the presence of a palladiumcatalyst (0), under or not under an inert gas atmosphere, in thepresence or in the absence of a base, in the presence or in the absenceof an additive.

In this scheme, W1a, M1, M1b, R10b, R20a, R21a, R22a and R23a have thesame definitions as above.

Method 12-1 of this method may be carried out in a manner similar toMethod K described above, and Method 12-2 may be carried out in a mannersimilar to Method K described above.

When a compound of the present invention is to be used as a medicament,it will normally be mixed with appropriate additives for use as aformulation.

However, this does not preclude the use of the compounds of theinvention by itself as medicament.

Such additives may include excipients, binders, lubricants,disintegrators, coloring agents, taste correctives, emulsifiers,surfactants, dissolving aids, suspending agents, isotonizing agents,buffering agents, antiseptics, antioxidants, stabilizers, absorptionaccelerators and the like which are commonly used in pharmaceuticals,and they may be added in appropriate combinations as desired.

As examples of such excipients there may be mentioned lactose, whitesoft sugar, glucose, corn starch, mannitol, sorbitol, starch, alphastarch, dextrin, crystalline cellulose, soft silicic anhydride, aluminumsilicate, calcium silicate, magnesium aluminometasilicate, calciumhydrogenphosphate, and the like.

As examples of binders there may be mentioned polyvinyl alcohol,methylcellulose, ethylcellulose, gum Arabic, tragacanth, gelatin,shellac, hydroxypropylmethylcellulose, hydroxypropylcellulose,carboxymethylcellulose sodium, polyvinylpyrrolidone, macrogol, and thelike.

As examples of lubricants there may be mentioned magnesium stearate,calcium stearate, sodium stearyl fumarate, talc, polyethylene glycol,colloidal silica, and the like.

As examples of disintegrators, there may be mentioned crystallinecellulose, agar, gelatin, calcium carbonate, sodium hydrogencarbonate,calcium citrate, dextrin, pectin, low-substitutedhydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulosecalcium, croscarmellose sodium, carboxymethyl starch, and carboxymethylstarch sodium, and the like.

As coloring agents there may be mentioned those approved for addition topharmaceuticals, such as iron sesquioxide, yellow iron sesquioxide,carmine, caramel, β-carotene, titanium oxide, talc, riboflavin sodiumphosphate, yellow aluminum lake and the like.

As taste correctives there may be mentioned cocoa powder, menthol,aromatic powders, mentha oil, borneol, powdered cinnamon bark, and thelike.

As emulsifiers or surfactants there may be mentioned stearyltriethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid,lecithin, glycerin monostearate, sucrose fatty acid esters, glycerinfatty acid esters, and the like.

As dissolving aids there may be mentioned polyethylene glycol, propyleneglycol, benzyl benzoate, ethanol, cholesterol, triethanolamine, sodiumcarbonate, sodium citrate, polysorbate 80, nicotinamide, and the like.

As suspending agents there may be mentioned the surfactants referred toabove, as well as hydrophilic polymers such as polyvinyl alcohol,polyvinylpyrrolidone, methylcellulose, hydroxymethylcellulose,hydroxyethylcellulose, hydroxypropylcellulose and the like.

As isotonizing agents there may be mentioned glucose, sodium chloride,mannitol, sorbitol and the like.

As buffering agents there may be mentioned buffering solutions ofphosphate, acetate, carbonate, citrate and the like.

As antiseptics there may be mentioned methylparaben, propylparaben,chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid,sorbic acid, and the like.

As antioxidants there may be mentioned sulfite, ascorbic acid,α-tocopherol, and the like.

As stabilizers there may be mentioned those commonly used inpharmaceuticals.

As absorption accelerators there may also be mentioned those commonlyused in pharmaceuticals.

The formulation may be in an oral form such as tablets, powders,granules, capsules, syrups, lozenges or inhalants, an externalapplication form such as suppository, ointment, eye salve, tape, eyedrop, nasal drop, ear drop, pap or lotion, or an injection.

An oral formulation will be formulated using an appropriate combinationof additives among those mentioned above. The surface thereof may alsobe coated if necessary.

An external application will be formulated using an appropriatecombination of additives among those mentioned above, and particularlyexcipients, binders, taste correctives, emulsifiers, surfactants,dissolving aids, suspending agents, isotonizing agents, antiseptics,antioxidants, stabilizers and absorption accelerators.

An injection will be formulated using an appropriate combination ofadditives among those mentioned above, and particularly emulsifiers,surfactants, dissolving aids, suspending agents, isotonizing agents,buffering agents, antiseptics, antioxidants, stabilizers and absorptionaccelerators.

When a compound of the invention is to be used as a drug, the dosagethereof will differ depending on the symptoms and age of the patient,but it will ordinarily be 0.15 to 5000 mg (preferably 0.5 to 1500 mg) inthe case of an oral formulation, 0.5 to 1500 mg (preferably 1.5 to 500mg) in the case of an external application, and 0.3 to 5000 mg(preferably 1 to 500 mg) in the case of an injection, per day,administered at once or divided over 2 to 6 times. For an oralformulation or injection, this represents the actual administered dose,while for an external application this represents the actual absorbeddose.

Compounds (1) and (100) according to the invention may be produced bythe specific processes described in the following examples. It is to beunderstood, however, that these examples merely serve as illustrationand are not intended to restrict the compounds of the invention underany circumstances.

EXAMPLES

Silica gel used in the following Examples are silica gel 60 (Merck &Co., Inc) or BW300 (Fuji Silysia Chemical Ltd.) unless otherwisementioned, and NH silica gel used are Chromatorex-NH silica gel (FujiSilysia Chemical Ltd.), propylamine-coated one.

Example 11-[2-(4,4-Dimethylcyclohexyl)-5-methoxyphenyl]-4-pentylpiperazinehydrochloride

4,4-Dimethylcyclohexanone

Reference: Bruce H. Lipshutz, John Keith, Patrick Papa, and RandallVivian, Tetrahedron Lett., 1998, 39, 4627.

1a Trifluoromethanesulfonic acid 4,4-dimethylcyclohex-1-enyl ester

A mixture of lithium bis(trimethylsilyl)amide (1M solution intetrahydrofuran, 172 mL, 172 mmol) and anhydrous tetrahydrofuran (400mL) was stirred, and then cooled to below −70° C. in a dry ice-acetonebath under a nitrogen atmosphere. A solution of4,4-dimethylcyclohexanone (18 g, 143 mmol) in anhydrous tetrahydrofuran(100 mL) was added dropwise to the solution over 30 minutes. Afterstirring for 2 hours and 10 minutes under the same conditions, N-phenylbis(trifluoromethanesulfonimide) (54 g, 150 mmol) was added to thereaction mixture, and stirring was continued for 16 hours while slowlywarmed to room temperature.

Saturated aqueous ammonium chloride was added to the reaction mixture toquench the reaction. Hexane and water were added to the mixture, and theorganic layer and aqueous layer were separated. The organic layer waswashed with brine and then dried over anhydrous magnesium sulfate. Theaqueous layer was re-extracted with hexane and treated in the samemanner as the organic layer. The two organic layers were combined, thedesiccant was filtered off and the filtrate was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give 26.8 g of the titlecompound as a light yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.97 (s, 6H), 1.54 (t, J=6.4 Hz, 2H),1.96-1.98 (m, 2H), 2.31-2.36 (m, 2H), 5.66-5.69 (m, 1H).

1b2-(4,4-Dimethylcyclohex-1-enyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane

To a mixture of trifluoromethanesulfonic acid4,4-dimethylcyclohex-1-enyl ester (19 g, 73.4 mmol) prepared in Example(1a), bis(pinacolato)diboron (21.5 g, 84.6 mmol),1,1′-bis(diphenylphosphino)ferrocene dichloropalladium(II)dichloromethane complex (3 g, 3.68 mmol) and potassium acetate (21.7 g,221 mmol) was added dioxane (200 mL), and the mixture was stirred undera nitrogen atmosphere at an external temperature of 80° C. for 17 hours.

After air-cooling the reaction mixture to room temperature, andinsoluble matters were filtered off through Celite. The resultantfiltrate was concentrated under reduced pressure, ethyl acetate andwater were added to the residue, and the organic layer was separatedoff. The organic layer was washed with brine and then dried overanhydrous sodium sulfate. The desiccant was filtered off and thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) togive 12.5 g of the title compound as a light yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.88 (s, 6H), 1.26 (s, 12H), 1.32 (t, J=6.4Hz, 2H), 1.85-1.87 (m, 2H), 2.10-2.15 (m, 2H), 6.49-6.51 (m, 1H).

1c 1-(4,4-Dimethylcyclohex-1-enyl)-4-methoxy-2-nitrobenzene

To a mixture of 4-bromo-3-nitroanisole (3.3 g, 14.1 mmol),2-(4,4-dimethylcyclohex-1-enyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane(4.0 g, 16.9 mmol) prepared in Example (1b), tripotassium phosphate (4.5g, 21.3 mmol) and 1,2-dimethoxyethane (30 mL) was addedtetrakis(triphenylphosphine)palladium(0) (0.82 g, 0.71 mmol) withstirring at room temperature under a nitrogen atmosphere. The mixturewas then stirred at an external temperature of 80° C. for 24 hours.

After cooling the reaction mixture to room temperature, brine was addedand the mixture was extracted with ethyl acetate. The organic layer wasdried over anhydrous magnesium sulfate, the desiccant was filtered offand then the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane) to give 3.5 g of the title compound as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.99 (s, 3H), 1.26 (s, 3H), 1.49 (t, J=6.4Hz, 2H), 1.78-1.90 (m, 2H), 2.20-2.26 (m, 2H), 3.84 (s, 3H), 5.49-5.54(m, 1H), 7.04 (dd, J=8.4, 2.8 Hz, 1H), 7.16 (d, J=8.4 Hz, 1H), 7.29 (d,J=2.8 Hz, 1H).

1d 2-(4,4-Dimethylcyclohex-1-enyl)-5-methoxyphenylamine

To a solution of1-(4,4-dimethylcyclohex-1-enyl)-4-methoxy-2-nitrobenzene (3.5 g, 13.4mmol) prepared in Example (1c) in ethanol (30 mL) were added a solution(5 mL) of aqueous ammonium chloride (2.9 g, 54 mmol) and iron powder(1.5 g, 26.8 mmol), and the mixture was stirred at an externaltemperature of 90° C. for 1 hour and 30 minutes. The reaction mixturewas passed through Celite, brine was added to the filtrate and themixture was extracted with ethyl acetate. The organic layer was driedover anhydrous magnesium sulfate, and the desiccant was filtered off.The filtrate was concentrated under reduced pressure to give 3.35 g ofthe title compound as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.99 (s, 3H), 1.26 (s, 3H), 1.50 (t, J=6.4Hz, 2H), 1.94-1.98 (m, 2H), 2.20-2.28 (m, 2H), 3.75 (s, 3H), 5.62-5.66(m, 1H), 6.24 (d, J=2.8 Hz, 1H), 6.29 (dd, J=8.4, 2.8 Hz, 1H), 6.88 (d,J=8.4 Hz, 1H).

The 2H of NH₂ could not be identified.

1e 1-[2-(4,4-Dimethylcyclohex-1-enyl)-5-methoxyphenyl]piperazine

A solution of 2-(4,4-dimethylcyclohex-1-enyl)-5-methoxyphenylamine (3.35g, 14.5 mmol) prepared in Example (1d) and bis(2-chloroethyl)aminehydrochloride (3.1 g, 17.4 mmol) in 1,2-dichlorobenzene (10 mL) wasstirred at 210° C. for 30 minutes. Nitrogen gas was blown into thereactor several times during the reaction to remove the excess hydrogenchloride gas in the reactor. The reaction mixture was cooled to roomtemperature, saturated aqueous sodium hydrogencarbonate was added andthe mixture was extracted with ethyl acetate. The organic layer wasdried over anhydrous magnesium sulfate. The desiccant was filtered offand the filtrate was concentrated under reduced pressure. The resultantresidue was purified by NH silica gel column chromatography (ethylacetate/hexane) to give 2.1 g of the title compound as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.97 (s, 6H), 1.44 (t, J=6.4 Hz, 2H),1.90-1.98 (m, 2H), 2.34-2.48 (m, 2H), 2.94-3.32 (m, 8H), 3.78 (s, 3H),5.58-5.66 (m, 1H), 6.48 (dd, J=8.4, 2.8 Hz, 1H), 6.50 (d, J=2.8 Hz, 1H),6.99 (d, J=8.4 Hz, 1H).

The 1H of NH could not be identified.

MS m/e (ESI) 301 (MH⁺).

1f1-[2-(4,4-Dimethylcyclohex-1-enyl)-5-methoxyphenyl]-4-pentylpiperazinehydrochloride

To a solution of1-[2-(4,4-dimethylcyclohex-1-enyl)-5-methoxyphenyl]piperazine (90 mg,0.29 mmol) prepared in Example (1e) in tetrahydrofuran (10 mL) wereadded valeraldehyde (31 mg, 0.36 mmol), sodium triacetoxyborohydride (95mg, 0.59 mmol) and acetic acid (35 mg, 0.59 mmol) in that order, and themixture was stirred for 3 hours. Saturated aqueous sodiumhydrogencarbonate was added to the reaction mixture and the mixture wasextracted with ethyl acetate. The organic layer was dried over anhydrousmagnesium sulfate, the desiccant was filtered off and then the filtratewas concentrated under reduced pressure. The resultant residue waspurified by NH silica gel column chromatography (ethyl acetate/hexane)to give 110 mg of1-[2-(4,4-dimethylcyclohex-1-enyl)-5-methoxyphenyl]-4-pentylpiperazineas a light yellow oil.

MS m/e (ESI) 371 (MH⁺).

The obtained compound was dissolved in ethyl acetate, a 4N solution ofhydrogen chloride in ethyl acetate was added and the mixture was stirredat room temperature for 30 minutes. The solvent was distilled off underreduced pressure, and then diethyl ether was added to the residue andthe mixture was filtered to give 50 mg of the title compound as a lightyellow solid.

¹H-NMR (400 MHz, CD₃OD) δ: 0.97 (s, 3H), 0.97 (t, J=7.2 Hz, 3H), 1.00(s, 3H), 1.34-1.50 (m, 8H), 1.72-1.85 (m, 4H), 2.94-3.40 (m, 6H),3.45-3.88 (m, 4H), 3.76 (s, 3H), 5.62-5.68 (m, 1H), 6.48-6.64 (m, 3H).MS m/e (ESI) 371 (MH⁺).

1g 1-[2-(4,4-Dimethylcyclohexyl)-5-methoxyphenyl]-4-pentylpiperazinehydrochloride

To a solution of1-[2-(4,4-dimethylcyclohex-1-enyl)-5-methoxyphenyl]-4-pentylpiperazinehydrochloride (44 mg) prepared in Example (1f) in methanol (5 mL) wasadded 10% palladium on carbon (100 mg, wet), and the mixture was stirredfor 17 hours under a hydrogen atmosphere at atmospheric pressure androom temperature. The reaction mixture was passed through Celite, andthe filtrate was concentrated under reduced pressure. Diethyl ether wasadded to the residue and the mixture was filtered to give 17 mg of thetitle compound as a light yellow solid.

¹H-NMR (400 MHz, CD₃OD) δ: 0.97 (s, 3H), 0.96 (t, J=7.2 Hz, 3H), 1.04(s, 3H), 1.36-1.86 (m, 14H), 2.8-2.95 (m, 1H), 3.06-3.40 (m, 10H), 3.77(s, 3H), 6.70 (d, J=2.8 Hz, 1H), 6.74 (dd, J=8.4, 2.8 Hz, 1H), 7.22 (d,J=8.4 Hz, 1H). MS m/e (ESI) 373 (MH⁺).

Example 2 4-Butyl-1-[2-(4-t-butylcyclohexyl)phenyl]piperazin-2-onehydrochloride

2a Trifluoromethanesulfonic acid 4-t-butylcyclohex-1-enyl ester

A solution of diisopropylamine (22 mL, 0.157 mol) in anhydroustetrahydrofuran (500 mL) was cooled to below −70° C. in a dryice-acetone bath under a nitrogen atmosphere. n-Butyllithium (1.56 Msolution in hexane, 100 mL, 0.156 mol) was slowly added dropwise to thestirred solution over 15 minutes. The reaction mixture was then warmedto −10° C. and then cooled to below −70° C. again. After stirring for 10minutes, a solution of 4-t-butylcyclohexanone (20.05 g, 0.13 mol) inanhydrous tetrahydrofuran (100 mL) was gradually added dropwise to thereaction mixture over 15 minutes. After stirring for 30 minutes, asolution of N-phenyl bis(trifluoromethanesulfonimide) (51.09 g, 0.143mol) in anhydrous tetrahydrofuran (200 mL) was gradually added dropwiseto the reaction mixture over 15 minutes and the mixture was stirred for30 minutes. The dry ice bath was then exchanged with an ice bath, andstirring was continued for 30 minutes and then for another 30 minutes atroom temperature.

Ethyl acetate and brine were added to the reaction mixture and themixture was extracted with ethyl acetate. The collected organic layerwas dried over anhydrous sodium sulfate. The desiccant was filtered offand the filtrate was concentrated under reduced pressure. The resultantresidue was purified by silica gel column chromatography (ethylacetate/hexane) to give 33.1 g of the title compound as a light yellowoil, in racemic form at the position of t-butyl.

¹H-NMR (400 MHz, CDCl₃) δ: 0.90 (s, 9H), 1.24-1.44 (m, 2H), 1.90-2.00(m, 2H), 2.16-2.25 (m, 1H), 2.32-2.46 (m, 2H), 5.72-5.76 (m, 1H).

2b 1-(4-t-Butylcyclohex-1-enyl)-2-nitrobenzene

A mixture of trifluoromethanesulfonic acid 4-t-butylcyclohex-1-enylester (7.16 g, 25 mmol) prepared in Example (2a), 2-nitrophenylboronicacid (5 g, 30 mmol), 2N aqueous sodium carbonate (25 mL), toluene (70mL) and ethanol (35 mL) was stirred at room temperature under a nitrogenatmosphere. To the mixture was addedtetrakis(triphenylphosphine)palladium(0) (1.5 g, 1.3 mmol). The mixturewas then stirred at an external temperature of 90° C. for 1 hour and 30minutes.

Ethyl acetate, water and brine were added to the reaction mixture andthe mixture was extracted with ethyl acetate. The collected organiclayer was dried over anhydrous sodium sulfate. The desiccant wasfiltered off and the filtrate was concentrated under reduced pressure.The resultant residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give 4.89 g of the title compound as ayellowish-brown oil, in racemic form at the position of t-butyl.

¹H-NMR (400 MHz, CDCl₃) δ: 0.90 (s, 9H), 1.32-1.44 (m, 2H), 1.86-1.97(m, 2H), 2.14-2.28 (m, 2H), 2.28-2.40 (m, 1H), 5.62-5.66 (m, 1H), 7.26(dd, J=7.6, 1.2 Hz, 1H), 7.34 (ddd, J=8.0, 7.6, 1.2 Hz, 1H), 7.49 (td,J=7.6, 1.2 Hz, 1H), 7.77 (dd, J=8.0, 1.2 Hz, 1H).

2c 2-(4-t-Butylcyclohexyl)phenylamine

A mixture of 1-(4-t-butylcyclohex-1-enyl)-2-nitrobenzene (4.89 g, 18.86mmol) prepared in Example (2b), 10% palladium on carbon (1.5 g, wet) andethyl acetate (25 mL) was stirred for 4 hours under a hydrogenatmosphere at atmospheric pressure and room temperature.

The reaction mixture was filtered, and the filtrate was concentratedunder reduced pressure. The resultant residue was purified by silica gelcolumn chromatography (ethyl acetate/hexane) to give 3.34 g of the titlecompound as a light brown oil, as a mixture of diastereomers at theposition of t-butylcyclohexyl.

¹H-NMR (400 MHz, CDCl₃) δ: 0.86 (s, 9H×0.6), 0.89 (s, 9H×0.4), 1.08-1.50(m, 4H), 1.60-2.14 (m, 5H), 2.36-2.46 (m, 1H×0.4), 2.90-2.96 (m,1H×0.6), 3.63 (brs, 2H), 6.64-6.69 (m, 1H), 6.73-6.79 (m, 1H), 6.98-7.04(m, 1H), 7.10 (dd, J=7.6, 1.2 Hz, 1H×0.4), 7.34 (dd, J=7.6, 1.2 Hz,1H×0.6).

2d 2-[2-(4-t-Butylcyclohexyl)phenylamino]ethanol

A mixture of 2-(4-t-butylcyclohexyl)phenylamine (1.2 g, 5.19 mmol)prepared in Example (2c), 2-bromoethanol (0.76 mL, 10.72 mmol),triethylamine (1.12 mL, 8.04 mmol) and toluene (20 mL) was heated atreflux for 16 hours and 20 minutes under a nitrogen atmosphere.

Ethyl acetate and water were added to the reaction mixture and themixture was extracted with ethyl acetate. The collected organic layerwas washed with brine and then dried over anhydrous sodium sulfate. Thedesiccant was filtered off and the filtrate was concentrated underreduced pressure. The resultant residue was purified by silica gelcolumn chromatography (ethyl acetate/hexane) to give 538 mg of the titlecompound as a light red oil, as a mixture of diastereomers at theposition of t-butylcyclohexyl.

¹H-NMR (400 MHz, CDCl₃) δ: 0.86 (s, 9H×0.6), 0.90 (s, 9H×0.4), 1.08-1.50(m, 4H), 1.60-2.12 (m, 5H), 2.36-2.45 (m, 1H×0.4), 2.91-2.96 (m,1H×0.6), 3.33-3.38 (m, 2H), 3.85-3.92 (m, 2H), 6.67 (dd, J=8.0, 1.2 Hz,1H×0.6), 6.68 (dd, J=8.0, 1.2 Hz, 1H×0.4), 6.75 (td, J=8.0, 1.2 Hz,1H×0.6), 6.76 (td, J=8.0, 1.2 Hz, 1H×0.4), 7.08-7.15 (m, 1H+1H×0.4),7.37 (dd, J=8.0, 1.2 Hz, 1H×0.6).

Each 1H of NH and OH could not be identified.

2eN-[2-(4-t-Butylcyclohexyl)phenyl]-2-chloro-N-(2-hydroxyethyl)acetamide

A solution of 2-[2-(4-t-butylcyclohexyl)phenylamino]ethanol (248 mg, 0.9mmol) prepared in Example (2d) in anhydrous tetrahydrofuran (5 mL) wascooled in an ice water bath under a nitrogen atmosphere. Chloroacetylchloride (0.08 mL, 1 mmol) was added thereto and the mixture was stirredfor 40 minutes.

Ethyl acetate, saturated aqueous sodium hydrogencarbonate and water wereadded to the reaction mixture and the mixture was extracted with ethylacetate. The collected organic layer was washed with brine and thendried over anhydrous sodium sulfate. The desiccant was filtered off andthe filtrate was concentrated under reduced pressure. The resultantresidue was purified by silica gel column chromatography (ethylacetate/hexane) to give 258 mg of the title compound as a colorless oil,as a mixture of diastereomers at the position of t-butylcyclohexyl.

¹H-NMR (400 MHz, CDCl₃) δ: 0.88 (s, 9H×0.4), 0.92 (s, 9H×0.6), 1.08-1.20(m, 1H), 1.21-1.32 (m, 2H), 1.42-1.94 (m, 6H), 2.54 (tt, J=12.0, 3.2 Hz,1H×0.4), 2.74-2.85 (m, 1H), 2.90-2.98 (m, 1H×0.6), 3.22 (dd, J=4.8, 4.0Hz, 1H×0.4), 3.25 (dd, J=4.8, 4.0 Hz, 1H×0.6), 3.69-3.90 (m, 4H),4.38-4.47 (m, 1H), 7.21 (d, J=7.6 Hz, 1H×0.6), 7.21 (d, J=7.6 Hz,1H×0.4), 7.23-7.29 (m, 1H), 7.37-7.43 (m, 1H+1H×0.4), 7.58 (dd, J=7.6,1.2 Hz, 1H×0.6).

2f N-[2-(4-t-Butylcyclohexyl)phenyl]-2-chloro-N-(2-oxoethyl)acetamide

A solution of oxalyl chloride (0.24 mL, 2.75 mmol) in anhydrousdichloromethane (5 mL) was cooled to below −65° C. in a dry ice-acetonebath under a nitrogen atmosphere. A solution of anhydrousdimethylsulfoxide (0.38 mL, 5.35 mmol) in anhydrous dichloromethane (5mL) was gradually added dropwise thereto over 8 minutes. The reactionmixture was then warmed to −20° C. and then cooled to below −65° C.again. A solution ofN-[2-(4-t-butylcyclohexyl)phenyl]-2-chloro-N-(2-hydroxyethyl)acetamide(256 mg, 0.727 mmol) prepared in Example (2e) in anhydrousdichloromethane (5 mL) was gradually added dropwise to the reactionmixture over 11 minutes. After stirring for 30 minutes, triethylamine(0.96 mL, 6.89 mmol) was added and the reaction mixture was graduallywarmed to room temperature.

Saturated aqueous ammonium chloride, ethyl acetate and water were addedto the reaction mixture and the mixture was extracted with ethylacetate. The collected organic layer was washed with a saturated aqueouscitric acid, water, saturated aqueous sodium hydrogencarbonate and brinein that order and then dried over anhydrous sodium sulfate. Thedesiccant was filtered off and the filtrate was concentrated underreduced pressure to give 303 mg of a crude product of the title compoundas a light yellow oil, as a mixture of diastereomers at the position oft-butylcyclohexyl. This was used without purification for the followingreaction.

2g 4-Butyl-1-[2-(4-t-butylcyclohexyl)phenyl]piperazin-2-onehydrochloride

A solution of the crude product ofN-[2-(4-t-butylcyclohexyl)phenyl]-2-chloro-N-(2-oxoethyl)acetamide (301mg) prepared in Example (2f) in 1,2-dichloroethane (7 mL) was cooled inan ice water bath under a nitrogen atmosphere. Molecular Sieve 4 Å (150mg), n-butylamine (0.091 mL, 0.921 mmol) and sodiumtriacetoxyborohydride (187 mg, 0.882 mmol) were added thereto in thatorder, and stirring was continued for 20 hours with slowly warmed toroom temperature.

Insoluble matters were filtered off, and then saturated aqueous ammoniumchloride, ethyl acetate and water were added to the filtrate and thefiltrate was extracted with ethyl acetate. The collected organic layerwas washed with saturated aqueous sodium hydrogencarbonate and brine inthat order and then dried over anhydrous sodium sulfate. The desiccantwas filtered off and the filtrate was concentrated under reducedpressure. The resultant residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give 163 mg of4-butyl-1-[2-(4-t-butylcyclohexyl)phenyl]piperazin-2-one as a lightyellow oil, as a mixture of diastereomers at the position oft-butylcyclohexyl.

¹H-NMR (400 MHz, CDCl₃) δ: 0.88 (s, 9H×0.4), 0.89 (s, 9H×0.6), 0.95 (t,J=7.2 Hz, 3H), 1.03-2.00 (m, 13H), 2.40-2.51 (m, 2H+1H×0.4), 2.64-2.77(m, 1H), 2.86-3.00 (m, 1H+1H×0.6), 3.16 (d, J=16.4 Hz, 1H×0.6), 3.24 (d,J=16.4 Hz, 1H×0.4), 3.37-3.45 (m, 2H), 3.62-3.73 (m, 1H), 7.12 (dd,J=7.6, 1.2 Hz, 1H), 7.21-7.36 (m, 2H+1H×0.4), 7.56 (dd, J=7.6, 1.2 Hz,1H×0.6).

The obtained compound was dissolved in ethyl acetate, and a 4N solutionof hydrogen chloride in ethyl acetate was added. The solution wasconcentrated under reduced pressure, and diethyl ether was added to theresultant residue to solidify. The solid was triturated by sonication,filtered and then dried under reduced pressure to give 102 mg of thetitle compound as a light brown solid, as a mixture of diastereomers atthe position of t-butylcyclohexyl.

MS m/e (ESI) 371 (MH⁺).

Example 34-[3-(4,4-Dimethylcyclohexyl)-4-(4-isobutylpiperazine-1-yl)phenyl]morpholinehydrochloride

3a 1-(4,4-Dimethylcyclohex-1-enyl)-2-nitrobenzene

To a solution of 2-nitrophenylboronic acid (14.2 g, 85.19 mmol) intoluene (250 mL)-ethanol (125 mL) were added trifluoromethanesulfonicacid 4,4-dimethylcyclohex-1-enyl ester (20 g, 77.44 mmol) prepared inExample (1a), tetrakis(triphenylphosphine)palladium(0) (4.5 g, 3.87mmol) and 2N aqueous sodium carbonate (128 mL, 256 mmol). The mixturewas stirred at an external temperature of 100° C. for 1 hour and 45minutes under a nitrogen atmosphere.

After air-cooling the reaction mixture to room temperature, it waspassed through Celite and insoluble matters were filtered off. Ethylacetate and water were added to the resultant filtrate and the filtratewas extracted with ethyl acetate.

The collected organic layer was washed with water and brine in thatorder and then dried over anhydrous magnesium sulfate. The desiccant wasfiltered off, and the filtrate was concentrated under reduced pressure.The resultant residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give 16.3 g of the title compound as a brownoil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.00 (s, 6H), 1.51 (t, J=6.4 Hz, 2H),1.92-1.94 (m, 2H), 2.24-2.29 (m, 2H), 5.55-5.57 (m, 1H), 7.27 (dd,J=7.6, 1.6 Hz, 1H), 7.34 (ddd, J=7.6, 7.6, 1.6 Hz, 1H), 7.50 (ddd,J=7.6, 7.6, 1.6 Hz, 1H), 7.77 (dd, J=7.6, 1.6 Hz, 1H).

3b 2-(4,4-Dimethylcyclohexyl)phenylamine

A mixture of 1-(4,4-dimethylcyclohex-1-enyl)-2-nitrobenzene (16.3 g,70.5 mmol) prepared in Example (3a), 10% palladium on carbon (1 g, wet)and ethyl acetate (100 mL) was stirred for 14 hours and 30 minutes undera hydrogen atmosphere at atmospheric pressure and room temperature.

The reaction mixture was filtered and the filtrate was concentratedunder reduced pressure. A mixture of the resultant residue, 10%palladium on carbon (3 g, wet) and ethyl alcohol (200 mL) was stirredfor 30 hours and 30 minutes under a hydrogen atmosphere at atmosphericpressure and room temperature.

After the reaction completed, the reaction mixture was filtered, and thefiltrate was concentrated under reduced pressure. The resultant residuewas purified by silica gel column chromatography (ethyl acetate/hexane)to give 11.79 g of the title compound as a light yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 0.97 (s, 3H), 0.99 (s, 3H), 1.36 (td, J=13.2,4.0 Hz, 2H), 1.47-1.73 (m, 6H), 2.38 (tt, J=11.6, 3.6 Hz, 1H), 3.63(brs, 2H), 6.68 (dd, J=7.6, 1.6 Hz, 1H), 6.77 (ddd, J=7.6, 7.6, 1.6 Hz,1H), 7.01 (ddd, J=7.6, 7.6, 1.6 Hz, 1H), 7.14 (dd, J=7.6, 1.6 Hz, 1H).

3c 1-[2-(4,4-Dimethylcyclohexyl)phenyl]piperazine

To a solution of 2-(4,4-dimethylcyclohexyl)phenylamine (11.79 g, 57.98mmol) prepared in Example (3b) in 1,2-dichlorobenzene (30 mL) was addedbis(2-chloroethyl)amine hydrochloride (12.42 g, 69.58 mmol), and themixture was stirred at an external temperature of 200° C. for 2 hoursand 30 minutes under a nitrogen atmosphere. During the reaction,nitrogen was passed through the reactor several times to remove thehydrogen chloride gas.

After air-cooling the reaction mixture to room temperature, ethylacetate and saturated aqueous sodium hydrogencarbonate were added andthe mixture was extracted with ethyl acetate. The collected organiclayer was washed with water and brine in that order and then dried overanhydrous sodium sulfate. The desiccant was filtered off, and thefiltrate was concentrated under reduced pressure. The resultant residuewas purified by NH silica gel column chromatography (ethylacetate/hexane) to give 12.15 g of the title compound as a brown oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.97 (s, 3H), 1.01 (s, 3H), 1.34 (td, J=12.8,4.4 Hz, 2H), 1.48-1.68 (m, 6H), 2.82-2.84 (m, 4H), 2.95-3.03 (m, 5H),7.05-7.27 (m, 4H).

The 1H of NH could not be identified.

3d 4-[2-(4,4-Dimethylcyclohexyl)phenyl]piperazine-1-carboxylic acidt-butyl ester

A mixture of 1-[2-(4,4-dimethylcyclohexyl)phenyl]piperazine (11 g, 40.4mmol) prepared in Example (3c), triethylamine (6.2 mL, 44.4 mmol),4-dimethylaminopyridine (247 mg, 2.02 mmol) and dichloromethane (180 mL)was stirred at an external temperature of 0° C. under a nitrogenatmosphere. A mixture of di-t-butyl dicarbonate (9.7 g, 44.4 mmol) anddichloromethane (20 mL) was added thereto.

After stirring for 2 hours and 50 minutes under the same conditions,saturated aqueous sodium hydrogencarbonate was added to the reactionmixture and the mixture was extracted with dichloromethane. Thecollected organic layer was washed with brine and then dried overanhydrous sodium sulfate. The desiccant was filtered off, and thefiltrate was concentrated under reduced pressure. The resultant residuewas purified by silica gel column chromatography (ethyl acetate/hexane)to give 14.89 g of the title compound as a light yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.96 (s, 3H), 1.01 (s, 3H), 1.31 (td, J=12.8,4.4 Hz, 2H), 1.49 (s, 9H), 1.49-1.69 (m, 6H), 2.81 (brs, 4H), 2.95-3.02(m, 1H), 3.57 (brs, 4H), 7.06 (dd, J=7.6, 1.6 Hz, 1H), 7.10 (ddd, J=7.6,7.6, 1.6 Hz, 1H), 7.16 (ddd, J=7.6, 7.6, 2.0 Hz, 1H), 7.28 (dd, J=7.6,2.0 Hz, 1H).

3e 4-[4-Bromo-2-(4,4-dimethylcyclohexyl)phenyl]piperazine-1-carboxylicacid t-butyl ester

A mixture of 4-[2-(4,4-dimethylcyclohexyl)phenyl]piperazine-1-carboxylicacid t-butyl ester (8 g, 21.5 mmol) prepared in Example (3d), sodiumacetate (17.6 g, 215 mmol) and methanol (300 mL) was stirred at anexternal temperature of room temperature under a nitrogen atmosphere.Bromine (1.1 mL, 21.5 mmol) was added dropwise thereto over 20 minutes,and the mixture was stirred for 17 hours under the same conditions.Sodium acetate (8.8 g, 107.5 mmol) was added thereto, and then bromine(0.4 mL, 7.8 mmol) was added dropwise and the mixture was stirred for 1hour under the same conditions.

A saturated aqueous solution of sodium sulfite was added to the reactionmixture and the mixture was extracted with ethyl acetate. The collectedorganic layer was washed with brine and then dried over anhydrousmagnesium sulfate. The desiccant was filtered off, and the filtrate wasconcentrated under reduced pressure. The resultant residue was purifiedby silica gel column chromatography (ethyl acetate/hexane) to give 7.97g of the title compound as a light yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 0.96 (s, 3H), 1.01 (s, 3H), 1.24-1.34 (m,2H), 1.41-1.64 (m, 6H), 1.49 (s, 9H), 2.77 (brs, 4H), 2.89-2.97 (m, 1H),3.55 (brs, 4H), 6.92 (d, J=8.4 Hz, 1H), 7.25 (dd, J=8.4, 2.4 Hz, 1H),7.35 (d, J=2.4 Hz, 1H).

3f4-[2-(4,4-Dimethylcyclohexyl)-4-morpholin-4-ylphenyl]piperazine-1-carboxylicacid t-butyl ester

A mixture of4-[4-bromo-2-(4,4-dimethylcyclohexyl)phenyl]piperazine-1-carboxylic acidt-butyl ester (1 g, 2.22 mmol) prepared in Example (3e), morpholine (290mg, 3.32 mmol), sodium t-butoxide (533 mg, 5.55 mmol), palladium(II)acetate (50 mg, 0.222 mmol), tri-t-butylphosphonium tetrafluoroborate(193 mg, 0.666 mmol) and xylene (10 mL) was stirred at an externaltemperature of 100° C. for 1 hour and 15 minutes under a nitrogenatmosphere.

After air-cooling the reaction mixture to room temperature, the mixturewas passed through Celite and insoluble matters were filtered off, andthen the resultant filtrate was concentrated under reduced pressure. Theresultant residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give 864 mg of the title compound as a yellowsolid.

¹H-NMR (400 MHz, CDCl₃) δ: 0.96 (s, 3H), 1.01 (s, 3H), 1.23-1.66 (m,8H), 1.48 (s, 9H), 2.75 (s, 4H), 2.93-3.01 (m, 1H), 3.12 (m, 4H), 3.49(brs, 4H), 3.86 (m, 4H), 6.70 (dd, J=8.8, 2.8 Hz, 1H), 6.83 (d, J=2.8Hz, 1H), 7.01 (d, J=8.8 Hz, 1H).

3g 4-[3-(4,4-Dimethylcyclohexyl)-4-piperazin-1-ylphenyl]morpholine

A solution of4-[2-(4,4-dimethylcyclohexyl)-4-morpholin-4-ylphenyl]piperazine-1-carboxylicacid t-butyl ester (864 mg, 1.89 mmol) prepared in Example (3f) in ethylacetate (15 mL)-dichloromethane (2 mL) was stirred at room temperatureunder a nitrogen atmosphere. A 4N solution of hydrogen chloride in ethylacetate (15 mL, 60 mmol) was added dropwise thereto, and the mixture wasstirred 12 hours under the same conditions.

After the reaction completed, saturated aqueous sodium carbonate wasadded to the reaction mixture to make the mixture basic. Chloroform andwater were added thereto and the mixture was extracted with chloroform.The collected organic layer was washed with brine and then dried overanhydrous sodium sulfate. The desiccant was filtered off and thefiltrate was concentrated under reduced pressure. The resultant residuewas purified by NH silica gel column chromatography (ethylacetate/hexane) to give 621 mg of the title compound as a colorlesssolid.

¹H-NMR (400 MHz, CDCl₃) δ: 0.97 (s, 3H), 1.01 (s, 3H), 1.31-1.64 (m,8H), 2.77-2.93 (m, 4H), 2.96-3.01 (m, 5H), 3.11-3.14 (m, 4H), 3.85-3.87(m, 4H), 6.72 (dd, J=8.8, 2.8 Hz, 1H), 6.84 (d, J=2.8 Hz, 1H), 7.07 (d,J=8.8 Hz, 1H).

The 1H of NH could not be identified.

3h4-[3-(4,4-Dimethylcyclohexyl)-4-(4-isobutylpiperazine-1-yl)phenyl]morpholinehydrochloride

To a mixture of4-[3-(4,4-dimethylcyclohexyl)-4-piperazin-1-ylphenyl]morpholine (100 mg,0.28 mmol) prepared in Example (3g), isobutylaldehyde (40 mg, 0.559mmol) and tetrahydrofuran (2 mL) was added sodium triacetoxyborohydride(119 mg, 0.559 mmol) at room temperature under a nitrogen atmosphere.

After stirring for 2 hours and 50 minutes, saturated aqueous sodiumhydrogencarbonate and water were added to the reaction mixture and themixture was extracted with ethyl acetate. The collected organic layerwas washed with water and brine in that order and then dried overanhydrous sodium sulfate. The desiccant was filtered off, and thefiltrate was concentrated under reduced pressure. The resultant residuewas purified by NH silica gel column chromatography (ethylacetate/hexane) to give 114 mg of4-[3-(4,4-dimethylcyclohexyl)-4-(4-isobutylpiperazine-1-yl)phenyl]morpholineas a colorless solid.

¹H-NMR (400 MHz, CDCl₃) δ: 0.93 (d, J=6.4 Hz, 6H), 0.97 (s, 3H), 1.01(s, 3H), 1.34 (td, J=12.8, 4.8 Hz, 2H), 1.43-1.62 (m, 6H), 1.83 (dq,J=7.2, 6.4 Hz, 1H), 2.16 (d, J=7.2 Hz, 2H), 2.53 (brs, 4H), 2.82-2.85(m, 4H), 2.93-3.01 (m, 1H), 3.11-3.13 (m, 4H), 3.85-3.87 (m, 4H), 6.71(dd, J=8.8, 2.8 Hz, 1H), 6.83 (d, J=2.8 Hz, 1H), 7.09 (d, J=8.8 Hz, 1H).

This product was dissolved in a mixed solvent of ethyl acetate anddichloromethane, and then a 4N solution of hydrogen chloride in ethylacetate was added. The produced hydrochloride was filtered to give 127mg of the title compound as a colorless solid.

MS m/e (ESI) 414 (MH⁺).

Example 41-Butyl-4-[2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazinehydrochloride

4a Trifluoromethanesulfonic acid 3,3,5,5-tetramethylcyclohex-1-enylester

A solution of 3,3,5,5-tetramethylcyclohexanone (12.8 g, 82.98 mmol) inanhydrous tetrahydrofuran (300 mL) was cooled to below −70° C. in a dryice-acetone bath under a nitrogen atmosphere. To the stirred solutionwas gradually added dropwise lithium bis(trimethylsilyl)amide (1Msolution in tetrahydrofuran, 100 mL, 100 mmol) over 15 minutes. Afterstirring for 40 minutes under the same conditions, a solution ofN-phenyl bis(trifluoromethanesulfonimide) (32.51 g, 91 mmol) inanhydrous tetrahydrofuran (150 mL) was added to the reaction mixture,and stirring was continued for 13 hours and 30 minutes with slowlywarmed to room temperature.

Ethyl acetate and brine were added to the reaction mixture and themixture was extracted with ethyl acetate. The collected organic layerwas dried over anhydrous sodium sulfate. The desiccant was filtered offand the filtrate was concentrated under reduced pressure. The resultantresidue was purified by silica gel column chromatography (ethylacetate/hexane) to give 23.65 g of the title compound as a colorlessoil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.04 (s, 6H), 1.09 (s, 6H), 1.35 (s, 2H),2.08 (s, 2H), 5.51 (s, 1H).

4b4,4,5,5-Tetramethyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)-[1,3,2]dioxaborolane

To a solution of trifluoromethanesulfonic acid3,3,5,5-tetramethylcyclohex-1-enyl ester (45.94 g, 0.16 mol) prepared inExample (4a) in dioxane (500 mL) were added bis(pinacolato)diboron (44.9g, 0.177 mol), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane complex (4 g, 4.9 mmol) andpotassium acetate (47.3 g, 0.482 mol), the mixture was stirred at anexternal temperature of 80° C. for 16 hours and 30 minutes.

Ethyl acetate, water and brine were added to the reaction mixture andthe mixture was extracted with ethyl acetate. The collected organiclayer was dried over anhydrous sodium sulfate. The desiccant wasfiltered off and the filtrate was concentrated under reduced pressure.The resultant residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give 39.27 g of the title compound as a lightyellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 0.92 (s, 6H), 1.01 (s, 6H), 1.27 (s, 12H),1.31 (s, 2H), 1.84 (d, J=1.6 Hz, 2H), 6.26 (t, J=1.6 Hz, 1H).

4c 4-(2-Hydroxyphenyl)piperazine-1-carboxylic acid t-butyl ester

A suspension of 2-(1-piperazino)phenol (3.56 g, 20 mmol) in acetonitrile(15 mL) was stirred at room temperature. A solution of di-t-butyldicarbonate (4.8 g, 22 mmol) in acetonitrile (15 mL) was added thereto.

After stirring for 1 hour, insoluble matters were filtered off and thefiltrate was concentrated. Hexane was added to the residue prior tosonication. The resultant solid was filtered and dried under reducedpressure to give a crude product of the title compound (5.35 g) as alight brown solid.

¹H-NMR (400 MHz, CDCl₃) δ: 1.49 (s, 9H), 2.82 (t, J=4.8 Hz, 4H), 3.59(t, J=4.8 Hz, 4H), 6.87 (td, J=7.6, 1.2 Hz, 1H), 6.96 (dd, J=8.0, 1.2Hz, 1H), 7.07-7.14 (m, 2H).

The 1H of OH could not be identified.

4d 4-(2-Trifluoromethanesulfonyloxyphenyl)piperazine-1-carboxylic acidt-butyl ester

A mixture of 4-(2-hydroxyphenyl)piperazine-1-carboxylic acid t-butylester (4.61 g, 16.56 mmol) prepared in Example (4c), triethylamine (11.5mL, 82.5 mmol) and dichloromethane (100 mL) was cooled in an ice bathunder a nitrogen atmosphere. Trifluoromethanesulfonic anhydride (4 mL,23.78 mmol) was gradually added dropwise over 40 minutes with stirringthe mixture.

After stirring for 17 minutes under the same conditions, saturatedaqueous ammonium chloride, ethyl acetate and water were added to thereaction mixture and the mixture was extracted with ethyl acetate. Thecollected organic layer was washed twice with saturated aqueous ammoniumchloride, subsequently washed with brine, and then dried over anhydroussodium sulfate. The desiccant was filtered off and the filtrate wasconcentrated under reduced pressure. The resultant residue was purifiedby silica gel column chromatography (ethyl acetate/hexane) to give 5.54g of the title compound as a light yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 1.48 (s, 9H), 2.95 (t, J=4.8 Hz, 4H), 3.62(t, J=4.8 Hz, 4H), 7.10-7.16 (m, 2H), 7.18 (dd, J=8.0, 1.6 Hz, 1H), 7.33(ddd, J=7.2, 7.2, 1.6 Hz, 1H).

4e4-[2-(3,3,5,5-Tetramethylcyclohex-1-enyl)phenyl]piperazine-1-carboxylicacid t-butyl ester

A mixture of4-(2-trifluoromethanesulfonyloxyphenyl)piperazine-1-carboxylic acidt-butyl ester (6.16 g, 15 mmol) prepared in Example (4d),4,4,5,5-tetramethyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)-[1,3,2]dioxaborolane(4.6 g, 17.41 mmol) prepared in Example (4b), tripotassium phosphate(3.2 g, 15 mmol), 1,2-dimethoxyethane (60 mL) and water (3 mL) wasstirred at room temperature under a nitrogen atmosphere.Tetrakis(triphenylphosphine)palladium(0) (1.74 g, 1.5 mmol) was added tothe mixture. The mixture was then stirred at an external temperature of85° C. for 2 hours and 20 minutes.

Ethyl acetate and water were added to the reaction mixture and then thiswas passed through Celite and filtered. The organic extract from thefiltrate was dried over anhydrous sodium sulfate. The desiccant wasfiltered off and the filtrate was concentrated under reduced pressure.The resultant residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give 5.78 g of the title compound as a lightyellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.02 (s, 6H), 1.07 (s, 6H), 1.40 (s, 2H),1.48 (s, 9H), 2.16 (d, J=1.6 Hz, 2H), 2.91 (t, J=5.2 Hz, 4H), 3.51 (t,J=5.2 Hz, 4H), 5.50 (t, J=1.6 Hz, 1H), 6.97 (dd, J=8.0, 1.2 Hz, 1H),7.01 (ddd, J=8.0, 8.0, 1.2 Hz, 1H), 7.09 (dd, J=8.0, 1.6 Hz, 1H), 7.20(ddd, J=8.0, 8.0, 1.6 Hz, 1H).

4f 1-[2-(3,3,5,5-Tetramethylcyclohex-1-enyl)phenyl]piperazine

A mixture of4-[2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazine-1-carboxylicacid t-butyl ester (1.78 g, 4.47 mmol) prepared in Example (4e),trifluoroacetic acid (5 mL, 64.9 mmol) and dichloromethane (15 mL) wasstirred at room temperature for 8 hours and 20 minutes.

The reaction mixture was made basic with a 5N aqueous sodium hydroxide,with cooled in an ice water bath. Ethyl acetate and water were thenadded and the mixture was extracted with ethyl acetate. The collectedorganic layer was washed with brine and then dried over anhydrous sodiumsulfate. The desiccant was filtered off and the filtrate wasconcentrated under reduced pressure to give a crude product of the titlecompound (1.62 g) as a light brown solid.

¹H-NMR (400 MHz, CDCl₃) δ: 1.03 (s, 6H), 1.07 (s, 6H), 1.41 (s, 2H),2.12 (d, J=1.6 Hz, 2H), 3.14 (t, J=6.0 Hz, 4H), 3.19 (t, J=6.0 Hz, 4H),5.49 (t, J=1.6 Hz, 1H), 7.01-7.11 (m, 3H), 7.22 (ddd, J=8.0, 7.2, 2.0Hz, 1H).

The 1H of NH could not be identified.

4g 1-Butyl-4-[2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazinehydrochloride

To a mixture of1-[2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazine (150 mg,0.503 mmol) prepared in Example (4f), butyraldehyde (0.09 mL, 1.011mmol) and tetrahydrofuran (7 mL) were added sodium triacetoxyborohydride(270 mg, 1.274 mmol) and acetic acid (0.03 mL, 0.524 mmol) in that orderat room temperature.

After stirring for 30 minutes, ethyl acetate, saturated aqueous sodiumhydrogencarbonate and water were added to the reaction mixture and themixture was extracted with ethyl acetate. The collected organic layerwas washed with brine and then dried over anhydrous sodium sulfate. Thedesiccant was filtered off and the filtrate was concentrated underreduced pressure. The resultant residue was purified by NH silica gelcolumn chromatography (ethyl acetate/hexane) to give 120 mg of1-butyl-4-[2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazine as acolorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.93 (t, J=7.2 Hz, 3H), 1.02 (s, 6H), 1.07(s, 6H), 1.34 (q, J=7.2 Hz, 2H), 1.40 (s, 2H), 1.48-1.55 (m, 2H), 2.17(d, J=1.6 Hz, 2H), 2.35-2.39 (m, 2H), 2.55 (brs, 4H), 3.02 (brs, 4H),5.51 (t, J=1.6 Hz, 1H), 6.96-7.02 (m, 2H), 7.07 (dd, J=7.2, 1.6 Hz, 1H),7.19 (ddd, J=8.0, 7.2, 1.6 Hz, 1H).

The product was dissolved in ethyl acetate and a 4N solution of hydrogenchloride in ethyl acetate was added. The solution was concentrated,diethyl ether and hexane were added to the resultant residue, and thecrystals were filtered. These were then dried with a vacuum pump to give124 mg of the title compound as colorless crystals.

MS m/e (ESI) 355 (MH⁺).

Example 51-Cyclopropylmethyl-4-[2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazinehydrochloride

To a mixture of1-[2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazine (40 mg, 0.134mmol) prepared in Example (4f), cyclopropanecarbaldehyde (0.014 mL,0.187 mmol) and tetrahydrofuran (3 mL) were added sodiumtriacetoxyborohydride (34 mg, 0.16 mmol) and acetic acid (0.008 mL,0.140 mmol) in that order at room temperature.

After stirring for 1 hour, ethyl acetate, saturated aqueous sodiumhydrogencarbonate and water were added to the reaction mixture and themixture was extracted with ethyl acetate. The collected organic layerwas concentrated under reduced pressure, and the resultant residue waspurified by NH silica gel column chromatography (ethyl acetate/hexane)to give 38 mg of1-cyclopropylmethyl-4-[2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazine.The target compound was confirmed by TLC and used for the followingprocedure.

The compound was dissolved in dichloromethane, and a 4N solution ofhydrogen chloride in ethyl acetate was added. The solution wasconcentrated, and diethyl ether was added to the resultant residue tocrystallize. Hexane was added thereto and supernatant diethylether-hexane solution was removed. The resultant residual solid wasdried under reduced pressure to give 35 mg of the title compound ascolorless crystals.

MS m/e (ESI) 353 (MH⁺).

Example 61-[2-(4,4-Diethylcyclohexyl)-5-methoxyphenyl]-4-(tetrahydropyran-4-ylmethyl)piperazinehydrochloride

4,4-Diethyl-2-cyclohexenone

Reference: Michael E. Flaugh, Thomas A. Crowell, and Diane S. Farlow, J.Org. Chem., 1980, 45, 5399.

6a 4,4-Diethylcyclohexanone

A mixture of 4,4-diethyl-2-cyclohexenone (1 g, 6.57 mmol), 10% palladiumon carbon (60 mg, wet) and ethyl acetate (15 mL) was stirred for 26hours under a hydrogen atmosphere at atmospheric pressure and roomtemperature.

The reaction mixture was filtered, and then the filtrate wasconcentrated under reduced pressure to give a crude product of the titlecompound (720 mg) as a brown oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.85 (t, J=7.6 Hz, 6H), 1.43 (q, J=7.6 Hz,4H), 1.65 (dd, J=7.2, 7.2 Hz, 4H), 2.31 (dd, J=7.2, 7.2 Hz, 4H).

6b Trifluoromethanesulfonic acid 4,4-diethylcyclohex-1-enyl ester

A solution of 4,4-diethylcyclohexanone (720 mg, 4.67 mmol) prepared inExample (6a) in anhydrous tetrahydrofuran (20 mL) was cooled to below−70° C. in a dry ice-acetone bath under a nitrogen atmosphere, and thenstirred. Lithium bis(trimethylsilyl)amide (1M solution intetrahydrofuran, 5.6 mL, 5.6 mmol) was gradually added dropwise to thissolution. After stirring for 60 minutes under the same conditions,N-phenyl bis(trifluoromethanesulfonimide) (1.75 g, 4.9 mmol) was addedto the reaction mixture, and stirring was continued for 27 hours withslowly warmed to room temperature.

Saturated aqueous ammonium chloride was added to the reaction mixture.Ethyl acetate and brine were then added to the reaction mixture and theorganic layer was separated off. After washing the organic layer withdiluted hydrochloric acid and saturated aqueous sodium hydrogencarbonatein that order, it was dried over anhydrous magnesium sulfate. Thedesiccant was filtered off and the filtrate was concentrated underreduced pressure. The resultant residue was purified by silica gelcolumn chromatography (ethyl acetate/hexane) to give 710 mg of the titlecompound as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.80 (t, J=7.6 Hz, 6H), 1.21-1.40 (m, 4H),1.55 (t, J=6.6 Hz, 2H), 1.95 (dt, J=4.0, 2.8 Hz, 2H), 2.25-2.30 (m, 2H),5.63-5.66 (m, 1H).

6c2-(4,4-Diethylcyclohex-1-enyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane

To a solution of trifluoromethanesulfonic acid4,4-diethylcyclohex-1-enyl ester (5.11 g, 17.8 mmol) prepared in Example(6b) in dioxane (60 mL) were added bis(pinacolato)diboron (5.2 g, 20.5mmol), 1,1′-bis(diphenylphosphino)ferrocene dichloropalladium(II)dichloromethane complex (580 mg, 0.71 mmol) and potassium acetate (5.3g, 53.5 mmol), and the mixture was stirred at an external temperature of90° C. for 4 hours.

The reaction mixture was air-cooled to room temperature, and insolublematters were filtered off. Ethyl acetate and water were added to theresultant filtrate and the organic layer was separated off. The organiclayer was washed with brine and then dried over anhydrous magnesiumsulfate. The desiccant was filtered off and the filtrate wasconcentrated under reduced pressure. The resultant residue was purifiedby silica gel column chromatography (ethyl acetate/hexane) to give 4.16g of the title compound as white crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 0.76 (t, J=7.6 Hz, 6H), 1.13-1.37 (m, 18H),1.84-1.86 (m, 2H), 2.05-2.10 (m, 2H), 6.48-6.50 (m, 1H).

6d 1-(4,4-Diethylcyclohex-1-enyl)-4-methoxy-2-nitrobenzene

A mixture of 4-bromo-3-nitroanisole (2 g, 8.62 mmol),2-(4,4-diethylcyclohex-1-enyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane(2.7 g, 10.3 mmol) prepared in Example (6c), tripotassium phosphate (2.7g, 13.0 mmol) and 1,2-dimethoxyethane (20 mL) was stirred at roomtemperature under a nitrogen atmosphere, and thentetrakis(triphenylphosphine)palladium(0) (0.5 g, 0.43 mmol) was added.The mixture was then stirred at an external temperature of 80° C. for 26hours.

After cooling the reaction mixture, brine was added and the mixture wasextracted with ethyl acetate. The organic layer was dried over anhydrousmagnesium sulfate. The desiccant was filtered off and the filtrate wasconcentrated under reduced pressure. The resultant residue was purifiedby silica gel column chromatography (ethyl acetate/hexane) to give 2.4 gof the title compound as a light yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.82 (t, J=7.2 Hz, 6H), 1.22-1.54 (m, 6H),1.87-1.94 (m, 2H), 2.14-2.20 (m, 2H), 3.84 (s, 3H), 5.48-5.54 (m, 1H),7.04 (dd, J=8.4, 2.8 Hz, 1H), 7.16 (d, J=8.4 Hz, 1H), 7.29 (d, J=2.8 Hz,1H).

6e 2-(4,4-Diethylcyclohex-1-enyl)-5-methoxyphenylamine

To a solution of 1-(4,4-diethylcyclohex-1-enyl)-4-methoxy-2-nitrobenzene(2.4 g, 8.3 mmol) prepared in Example (6d) in ethanol (20 mL) were addedan aqueous solution (5 mL) of ammonium chloride (2.2 g, 41 mmol) andiron powder (1.2 g, 20.7 mmol), and the mixture was stirred at anexternal temperature of 90° C. for 1 hour. The reaction mixture waspassed through Celite for filtration, and then brine was added to thefiltrate and the mixture was extracted with ethyl acetate. The organiclayer was dried over anhydrous magnesium sulfate, the desiccant wasfiltered off, and then the filtrate was concentrated under reducedpressure to give 2.6 g of the title compound as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.82 (t, J=7.2 Hz, 6H), 1.21-1.56 (m, 6H),1.92-1.96 (m, 2H), 2.16-2.22 (m, 2H), 3.75 (s, 3H), 5.61-5.65 (m, 1H),6.24 (d, J=2.8 Hz, 1H), 6.29 (dd, J=8.4, 2.8 Hz, 1H), 6.87 (d, J=8.4 Hz,1H).

The 2H of NH₂ could not be identified.

6f 1-[2-(4,4-Diethylcyclohex-1-enyl)-5-methoxyphenyl]piperazine

A solution of 2-(4,4-diethylcyclohex-1-enyl)-5-methoxyphenylamine (2.6g, 10 mmol) prepared in Example (6e) and bis(2-chloroethyl)aminehydrochloride (2.2 g, 12 mmol) in 1,2-dichlorobenzene (10 mL) wasstirred at an external temperature of 210° C. Nitrogen gas was blowninto the reactor several times during the reaction to remove the excesshydrogen chloride gas in the reactor. After 1 hour, the reaction mixturewas cooled to room temperature, and then saturated aqueous sodiumhydrogencarbonate was added and the mixture was extracted with ethylacetate. The organic layer was dried over anhydrous magnesium sulfate.The desiccant was filtered off and the filtrate was concentrated underreduced pressure. The resultant residue was purified by NH silica gelcolumn chromatography (ethyl acetate/hexane) to give 1.4 g of the titlecompound as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.82 (t, J=7.2 Hz, 6H), 1.22-1.52 (m, 6H),1.90-1.96 (m, 2H), 2.38-2.46 (m, 2H), 2.78-3.04 (m, 8H), 3.79 (s, 3H),5.61-5.66 (m, 1H), 6.50 (dd, J=8.4, 2.8 Hz, 1H), 6.52 (d, J=2.8 Hz, 1H),6.99 (d, J=8.4 Hz, 1H).

The 1H of NH could not be identified.

MS m/e (ESI) 329 (MH⁺).

6g1-[2-(4,4-Diethylcyclohex-1-enyl)-5-methoxyphenyl]-4-(tetrahydropyran-4-ylmethyl)piperazinehydrochloride

To a solution of1-[2-(4,4-diethylcyclohex-1-enyl)-5-methoxyphenyl]piperazine (90 mg,0.27 mmol) prepared in Example (6f) in tetrahydrofuran (10 mL) wereadded tetrahydropyran-4-carbaldehyde (37 mg, 0.32 mmol), sodiumtriacetoxyborohydride (87 mg, 0.41 mmol) and acetic acid (32 mg, 0.57mmol) in that order, and the mixture was stirred at room temperature for1 hour and 30 minutes. Saturated aqueous sodium hydrogencarbonate wasadded to the reaction mixture and the mixture was extracted with ethylacetate. The organic layer was dried over anhydrous magnesium sulfate.The desiccant was filtered off and the filtrate was concentrated underreduced pressure. The resultant residue was purified by NH silica gelcolumn chromatography (ethyl acetate/hexane) to give 50 mg of1-[2-(4,4-diethylcyclohex-1-enyl)-5-methoxyphenyl]-4-(tetrahydropyran-4-ylmethyl)piperazineas a light yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.82 (t, J=7.2 Hz, 6H), 1.40-1.94 (m, 13H),2.22 (d, J=7.2 Hz, 2H), 2.35-2.58 (m, 6H), 2.94-3.18 (m, 4H), 3.38 (td,J=12, 2.0 Hz, 2H), 3.77 (s, 3H), 3.90-4.00 (m, 2H), 5.59-5.64 (m, 1H),6.47 (dd, J=8.4, 2.8 Hz, 1H), 6.51 (d, J=2.8 Hz, 1H), 6.97 (d, J=8.4 Hz,1H).

The obtained compound was dissolved in ethyl acetate, and then a 4Nsolution of hydrogen chloride in ethyl acetate was added and the mixturewas stirred at room temperature for 15 minutes. The solvent wasdistilled off under reduced pressure and the residual solid was washedwith diethyl ether. It was then filtered to give 50 mg of the titlecompound as a light yellow solid.

MS m/e (ESI) 427 (MH⁺).

6h1-[2-(4,4-Diethylcyclohexyl)-5-methoxyphenyl]-4-(tetrahydropyran-4-ylmethyl)piperazinehydrochloride

Ten percent of palladium on carbon (100 mg, wet) was added to a solutionof1-[2-(4,4-diethylcyclohex-1-enyl)-5-methoxyphenyl]-4-(tetrahydropyran-4-ylmethyl)piperazinehydrochloride (34 mg) prepared in Example (6g) in methanol (5 mL), andthe mixture was stirred for 13 hours under a hydrogen atmosphere atatmospheric pressure and room temperature. The reaction mixture waspassed through Celite for filtration, and the filtrate was concentratedunder reduced pressure. The residual solid was washed with diethylether. It was then filtered to give 34 mg of the title compound as alight yellow solid.

¹H-NMR (400 MHz, CD₃OD) δ: 0.82 (t, J=7.2 Hz, 3H), 0.83 (t, J=7.2 Hz,3H), 1.20-1.82 (m, 17H), 2.16-2.28 (m, 2H), 2.86-2.96 (m, 1H), 3.10-3.36(m, 6H), 3.48 (td, J=12, 2.0 Hz, 2H), 3.68 (d, J=7.2 Hz, 2H), 3.77 (s,3H), 3.98 (dd, J=7.2, 4.0 Hz, 2H), 6.72 (d, J=2.8 Hz, 1H), 6.74 (dd,J=8.4, 2.8 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H). MS m/e (ESI) 429 (MH⁺).

Example 71-Butyl-4-[2-(4-t-butylcyclohex-1-enyl)-4-(4-methoxypiperidin-1-yl)phenyl]piperazinehydrochloride

7a 4-Methoxypiperidine hydrochloride

4-hydroxypiperidine-1-carboxylic acid t-butyl ester (25.5 g, 127 mmol)was added to a mixed solution of anhydrous tetrahydrofuran (100 mL) anddimethylformamide (40 mL). The solution was cooled to 0° C. in an icebath with stirring. Sodium hydride (60% dispersion in oil, 7.6 g, 190mmol) was gradually added over 3 minutes. The reaction mixture waswarmed to room temperature, stirred for 70 minutes, and cooled to 0° C.again. A solution of methyl iodide (9.5 mL, 152 mmol) in anhydroustetrahydrofuran (20 mL)-dimethylformamide (5 mL) was gradually added tothe reaction mixture over 20 minutes. The ice bath was removed, and thereaction mixture was warmed to room temperature and stirred for 1 hour.

After the reaction, water and diethyl ether were added to the reactionmixture and the organic layer was separated off. The organic layer waswashed 3 times with water, and then once with brine and dried overanhydrous sodium sulfate. The desiccant was filtered off and thefiltrate was concentrated under reduced pressure.

Ethyl acetate (200 mL) was added to the residue, and the mixture wascooled to 0° C. and stirred. A 4N solution of hydrogen chloride in ethylacetate (100 mL) was then gradually added over 10 minutes, and thetemperature was slowly raised to room temperature.

After stirring for 13 hours, the reaction mixture was concentrated underreduced pressure. The residue was dissolved in a small amount ofdichloromethane. An excess of ethyl acetate was then added and theprecipitated solid was filtered out and dried under reduced pressure togive 17.0 g of the title compound as colorless crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 1.95-2.02 (m, 2H), 2.05-2.15 (m, 2H),3.14-3.30 (m, 4H), 3.32 (s, 3H), 3.52-3.57 (m, 1H).

The 1H of NH could not be identified.

7b 5-(4-Methoxypiperidin-1-yl)-2-nitrophenol

A mixture of 4-methoxypiperidine hydrochloride (9.10 g, 60.01 mmol)prepared in Example (7a), 5-fluoro-2-nitrophenol (6.91 g, 43.98 mmol)and dimethylformamide (12 mL) was stirred under a nitrogen atmosphere.Triethylamine (15.24 mL, 109.95 mmol) was added to the reaction mixtureand the mixture was stirred at an external temperature of 80° C. for 3hours and 30 minutes.

After the reaction, saturated aqueous ammonium chloride and a mixedsolvent of ethyl acetate-diethyl ether was added to the reactionmixture. The organic layer was separated off, and the aqueous layer wasextracted with diethyl ether. The obtained organic layers were combinedand dried over anhydrous sodium sulfate. The desiccant was filtered offand the filtrate was concentrated under reduced pressure. The resultantresidue was purified by silica gel column chromatography (ethylacetate/hexane) to give 37.36 g of the title compound as orangecrystals.

¹H-NMR (400 MHz, CDCl₃) δ: 1.60-1.68 (m, 2H), 1.83-1.90 (m, 2H), 3.26(ddd, J=13.2, 8.0, 3.6 Hz, 2H), 3.32 (s, 3H), 3.42-3.47 (m, 1H), 3.62(ddd, J=13.2, 7.6, 3.6 Hz, 2H), 6.24 (d, J=2.8 Hz, 1H), 6.36 (dd,J=10.0, 2.8 Hz, 1H), 7.87 (d, J=10.0 Hz, 1H).

The 1H of OH could not be identified.

7c Trifluoromethanesulfonic acid5-(4-methoxypiperidin-1-yl)-2-nitrophenyl ester

A mixture of 5-(4-methoxypiperidin-1-yl)-2-nitrophenol (2.35 g, 8.16mmol) prepared in Example (7b), triethylamine (5.7 mL, 40.9 mmol) anddichloromethane (50 mL) was stirred in an ice water bath, and thentrifluoromethanesulfonic anhydride (2 mL, 12.24 mmol) was graduallyadded dropwise for 15 minutes, and the mixture was stirred for 10minutes under the same conditions.

Saturated aqueous ammonium chloride was added to the reaction mixture,and then ethyl acetate and water were added and the organic layer wasseparated off. The organic layer was dried over anhydrous sodiumsulfate. The desiccant was filtered off and the filtrate wasconcentrated under reduced pressure. The resultant residue was purifiedby silica gel column chromatography (ethyl acetate/hexane) to give 3.276g of the title compound as an orange solid.

¹H-NMR (400 MHz, CDCl₃) δ: 1.66-1.74 (m, 2H), 1.84-1.92 (m, 2H), 3.27(ddd, J=13.2, 7.6, 3.6 Hz, 2H), 3.23 (s, 3H), 3.47 (m, 1H), 3.58 (ddd,J=12, 8.0, 3.6 Hz, 2H), 6.54 (d, J=2.8 Hz, 1H), 6.72 (dd, J=9.6, 2.8 Hz,1H), 8.07 (d, J=9.6 Hz, 1H).

7d 2-(4-t-Butylcyclohex-1-enyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane

To trifluoromethanesulfonic acid 4-t-butylcyclohex-1-enyl ester (55.0 g,192.1 mmol) prepared in Example (2a) were added bis(pinacolato)diboron(56.1 g, 220.9 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane complex (4.88 g, 5.98 mmol),potassium acetate (56.6 g, 576.3 mmol) and dioxane (400 mL), and themixture was stirred at an external temperature of 80° C. for 16 hours.

After the reaction, the reaction mixture was air-cooled to roomtemperature, ethyl acetate and water were added to the reaction mixture,and the organic layer was separated off. The obtained organic layer wasagain washed with water, and dried over anhydrous magnesium sulfate. Thedesiccant was filtered off and the filtrate was concentrated underreduced pressure. The resultant residue was purified by silica gelcolumn chromatography (ethyl acetate/hexane) to give 38.97 g of thetitle compound as a light yellow solid, in racemic form at the positionof t-butyl.

¹H-NMR (400 MHz, CDCl₃) δ: 0.85 (s, 9H), 1.00-1.43 (m, 14H), 1.78-1.90(m, 2H), 1.98-2.17 (m, 2H), 2.24-2.32 (m, 1H), 6.59 (dd, J=2.0 Hz, 1H).

7e 1-[3-(4-t-Butylcyclohex-1-enyl)-4-nitrophenyl]-4-methoxypiperidine

To a solution of trifluoromethanesulfonic acid5-(4-methoxypiperidin-1-yl)-2-nitrophenyl ester (3.276 g, 8.52 mmol)prepared in Example (7c) in 1,2-dimethoxyethane (80 mL) were added2-(4-t-butylcyclohex-1-enyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane(2.478 g, 9.38 mmol) prepared in Example (7d),tetrakis(triphenylphosphine)palladium(0) (492 mg, 0.426 mmol) andtripotassium phosphate (2.714 g, 12.79 mmol), and the mixture wasstirred at an external temperature of 90° C. for 2 hours and 30 minutesunder a nitrogen atmosphere.

After the reaction, brine and ethyl acetate were added to the reactionmixture. The organic layer was separated off and then dried overanhydrous sodium sulfate. The desiccant was filtered off and thefiltrate was concentrated under reduced pressure. The resultant residuewas purified by silica gel column chromatography (ethyl acetate/hexane)to give 1.87 g of the title compound as orange crystals, in racemic format the position of t-butyl.

¹H-NMR (400 MHz, CDCl₃) δ: 0.90 (s, 9H), 1.38-1.43 (m, 2H), 1.64-1.74(m, 2H), 1.86-2.00 (m, 3H), 2.13-2.33 (m, 4H), 3.21 (ddd, J=12.4, 8.4,3.6 Hz, 2H), 3.38 (s, 3H), 3.46 (m, 1H), 3.67 (ddd, J=11.2, 7.2, 3.6 Hz,2H), 5.57 (t, J=2.4 Hz, 1H), 6.54 (d, J=2.8 Hz, 1H), 6.72 (dd, J=9.6,2.8 Hz, 1H), 8.07 (d, J=9.6 Hz, 1H).

7f 2-(4-t-Butylcyclohex-1-enyl)-4-(4-methoxypiperidin-1-yl)phenylamine

1-[3-(4-t-butylcyclohex-1-enyl)-4-nitrophenyl]-4-methoxypiperidine (1.87g, 5.02 mmol) prepared in Example (7e), ammonium chloride (93.6 mg, 1.75mmol), a mixed solution of ethanol (30 mL)-water (10 mL) and iron powder(981 mg, 17.57 mmol) were added in turn, and the mixture was stirred atan external temperature of 90° C. for 2 hours under a nitrogenatmosphere.

Ammonium chloride (30 mg, 0.56 mmol) and iron powder (300 mg, 5.37 mmol)were added to the reaction mixture, and the mixture was stirred for 3hours and 15 minutes under the same conditions.

Insoluble matters of the reaction mixture were filtered, and then ethylacetate and brine were added to the filtrate. The organic layer wasseparated off and then dried over anhydrous sodium sulfate. Thedesiccant was filtered off and the filtrate was concentrated underreduced pressure. The resultant residue was purified by NH silica gelcolumn chromatography (ethyl acetate/hexane) to give 1.155 g of thetitle compound as a light yellow solid, in racemic form at the positionof t-butyl.

¹H-NMR (400 MHz, CDCl₃) δ: 0.90 (s, 9H), 1.24-1.42 (m, 2H), 1.66-1.76(m, 2H), 1.90-2.06 (m, 4H), 2.14-2.24 (m, 1H), 2.28-2.32 (m, 2H),2.72-2.80 (m, 2H), 3.26-3.37 (m, 3H), 3.37 (s, 3H), 5.75 (brs, 1H), 6.63(d, J=8.4 Hz, 1H), 6.67 (s, 1H), 6.71 (d, J=8.4 Hz, 1H).

The 2H of NH₂ could not be identified.

7g1-[2-(4-t-Butylcyclohex-1-enyl)-4-(4-methoxypiperidin-1-yl)phenyl]piperazine

To a solution of2-(4-t-butylcyclohex-1-enyl)-4-(4-methoxypiperidin-1-yl)phenylamine(1.155 g, 3.37 mmol) prepared in Example (7f) in 1,2-dichlorobenzene (15mL) was added bis(2-chloroethyl)amine hydrochloride (722 mg, 4.04 mmol),and the mixture was stirred at an external temperature of 200° C. undera nitrogen atmosphere.

The excess hydrogen chloride gas in the reactor was removed using astream of nitrogen several times during the reaction.

After 6 hours, the reaction mixture was cooled to room temperature.Aqueous potassium carbonate was added to the reaction mixture to makethe aqueous layer basic, and then ethyl acetate and a small amount ofmethanol were added. The organic layer was separated off and then driedover anhydrous sodium sulfate. The desiccant was filtered off and thefiltrate was concentrated under reduced pressure. The resultant residuewas purified by NH silica gel column chromatography (ethylacetate/hexane) to give 660 mg of the titled compound as a light yellowsolid, in racemic form at the position of t-butyl.

¹H-NMR (400 MHz, CDCl₃) δ: 0.84 (s, 9H), 1.12-1.32 (m, 2H), 1.58-1.66(m, 2H), 1.80-1.98 (m, 4H), 2.08-2.16 (m, 1H), 2.28-2.40 (m, 1H),2.59-2.62 (m, 1H), 2.76 (td, J=12.0, 2.8 Hz, 4H), 2.83-2.91 (m, 6H),3.22-3.28 (m, 1H), 3.31 (s, 3H), 3.36-3.42 (m, 2H), 5.63 (t, J=2.4 Hz,1H), 6.67 (d, J=3.2 Hz, 11H), 6.70 (dd, J=8.4, 3.2 Hz, 11H), 6.81 (d,J=8.4 Hz, 1H).

The 1H of NH could not be identified.

7h1-Butyl-4-[2-(4-t-butylcyclohex-1-enyl)-4-(4-methoxypiperidin-1-yl)phenyl]piperazinehydrochloride

To a solution of1-[2-(4-t-butylcyclohex-1-enyl)-4-(4-methoxypiperidin-1-yl)phenyl]piperazine(100 mg, 0.243 mmol) prepared in Example (7g) in tetrahydrofuran (3 mL)were added butyraldehyde (0.0281 mL, 0.316 mmol), sodiumtriacetoxyborohydride (87.1 mg, 0.316 mmol) and acetic acid (0.0267 mL,0.466 mmol), and the mixture was stirred at room temperature for 4 hoursand 30 minutes.

After the reaction completed, saturated aqueous sodium hydrogencarbonatewas added to the reaction mixture and the mixture was extracted 3 timeswith ethyl acetate. The obtained organic layers were combined and driedover anhydrous sodium sulfate. The desiccant was filtered off and thefiltrate was concentrated under reduced pressure. The resultant residuewas purified by NH silica gel column chromatography (ethylacetate/hexane) to give 103 mg of1-butyl-4-[2-(4-t-butylcyclohex-1-enyl)-4-(4-methoxypiperidin-1-yl)phenyl]piperazineas a colorless solid, in racemic form at the position of t-butyl.

¹H-NMR (400 MHz, CDCl₃) δ: 0.89-0.96 (m, 12H), 1.18-1.39 (m, 4H),1.48-1.60 (m, 2H), 1.64-1.74 (m, 2H), 1.86-2.06 (m, 4H), 2.14-2.23 (m,1H), 2.30-2.42 (m, 3H), 2.47-2.60 (m, 4H), 2.66-2.74 (m, 1H), 2.78-2.86(m, 2H), 2.89-3.06 (m, 4H), 3.28-3.35 (m, 1H), 3.37 (s, 3H), 3.41-3.48(m, 2H), 5.69 (brs, 1H), 6.73 (s, 1H), 6.76 (d, J=8.4 Hz, 1H), 6.89 (d,J=8.4 Hz, 1H).

The product was dissolved in ethyl acetate (3 mL), and then a 4Nsolution of hydrogen chloride in ethyl acetate (0.11 mL, 0.44 mmol) wasadded.

The reaction solvent was removed under reduced pressure, diethyl etherwas added and the resultant solid was filtered to give 83 mg of thetitle compound as a colorless solid, in racemic form at the position oft-butyl.

MS m/e (ESI) 468 (MH⁺).

Example 8 1-Butyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

8a 4-[2-(3,3,5,5-Tetramethylcyclohexyl)phenyl]piperazine-1-carboxylicacid t-butyl ester

A mixture of4-[2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazine-1-carboxylicacid t-butyl ester (3.87 g, 9.71 mmol) prepared in Example (4e), 10%palladium on carbon (2.3 g, wet), methanol (25 mL) and tetrahydrofuran(25 mL) was stirred for 22 hours and 30 minutes under hydrogenatmosphere at atmospheric pressure and room temperature.

After filtering the reaction mixture, the filtrate was concentrated.Ethyl acetate was added to the residue, the mixture was filtered again,and the filtrate was concentrated under reduced pressure to give a crudeproduct of the title compound (3.83 g) as a light yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.92 (s, 6H), 1.12 (s, 6H), 1.12-1.47 (m,6H), 1.49 (s, 9H), 2.83 (brs, 4H), 3.59 (tt, J=12.4, 2.8 Hz, 1H), 7.07(td, J=7.6, 1.2 Hz, 1H), 7.10 (dd, J=7.6, 1.2 Hz, 1H), 7.16 (td, J=7.6,2.0 Hz, 1H), 7.24 (dd, J=7.6, 2.0 Hz, 1H).

The 4H of the piperazine ring could not be identified.

MS m/e (ESI) 401 (MH⁺).

8b 1-[2-(3,3,5,5-Tetramethylcyclohexyl)phenyl]piperazine

A mixture of4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine-1-carboxylic acidt-butyl ester (9.79 g, 24.44 mmol) prepared in Example (8a),trifluoroacetic acid (25 mL, 346 mmol) and dichloromethane (50 mL) wasstirred at room temperature for 1 hour and 30 minutes.

After the reaction completed, the reaction mixture was cooled in an icewater bath and it was made basic with 5N aqueous sodium hydroxide. Ethylacetate and water were then added thereto and the mixture was extractedwith ethyl acetate. The collected organic layer was washed with brineand then dried over anhydrous sodium sulfate. The desiccant was filteredoff and the filtrate was concentrated under reduced pressure. Hexane wasadded to the resultant residue to precipitate crystals, and the crystalswere filtered and dried with a vacuum pump to give 4.94 g of the titlecompound as colorless crystals.

¹H-NMR (400 MHz, CDCl₃) for the lot of the above 4.94 g: δ: 0.94 (s,6H), 1.11 (s, 6H), 1.13-1.44 (m, 6H), 3.17 (brs, 4H), 3.35 (brs, 4H),3.47 (tt, J=12.4, 2.8 Hz, 1H), 7.10-7.30 (m, 4H).

The 1H of NH could not be identified.

After concentrating the mother liquor yielded at the filtration giving4.94 g of the titled compound, the resultant residue was purified by NHsilica gel column chromatography (ethyl acetate/hexane) to give 2.23 gof the title compound as colorless crystals.

¹H-NMR (400 MHz, CDCl₃) for the lot of the above 2.23 g: δ: 0.92 (s,6H), 1.13 (s, 6H), 1.17-1.35 (m, 4H), 1.41-1.46 (m, 2H), 2.84-2.86 (m,4H), 3.01-3.03 (m, 4H), 3.59 (tt, J=12.8, 2.8 Hz, 1H), 7.04-7.16 (m,3H), 7.21 (dd, J=7.6, 1.6 Hz, 1H).

The 1H of NH could not be identified.

8c 1-Butyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

To a solution of 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine(300 mg, 1.00 mmol) prepared in Example (8b) in tetrahydrofuran (20 mL)were added butyraldehyde (107 mg, 1.49 mmol), sodiumtriacetoxyborohydride (420 mg, 1.99 mmol) and acetic acid (60 mg, 0.99mmol) in that order, the mixture was stirred at room temperature for 13hours and 30 minutes. After the reaction completed, saturated aqueoussodium hydrogencarbonate was added to the reaction mixture and themixture was extracted with ethyl acetate. The organic layer was driedover anhydrous magnesium sulfate, and then the desiccant was filteredand the filtrate was concentrated under reduced pressure. The resultantresidue was purified by NH silica gel column chromatography (ethylacetate/heptane) to give 270 mg of1-butyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine as a lightyellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.92 (s, 6H), 0.94 (t, J=7.2 Hz, 3H), 1.12(s, 6H), 1.20-1.60 (m, 10H), 2.37-2.41 (m, 2H), 2.40-2.62 (brs, 4H),2.92 (t, J=4.8 Hz, 4H), 3.57 (tt, J=12.4, 2.8 Hz, 1H), 7.03-7.08 (m,1H), 7.09-7.16 (m, 2H), 7.19-7.22 (m, 1H).

The product was dissolved in dichloromethane (5 mL), and then a 4Nsolution of hydrogen chloride in ethyl acetate (0.21 mL, 0.83 mmol) wasadded and the mixture was stirred at room temperature for 30 minutes.The solvent of the reaction mixture was distilled off under reducedpressure to give a crude product of the title compound (290 mg) as alight yellow solid. Ethyl acetate (30 mL) was added to the obtainedcrude product (290 mg) and the mixture was stirred at an externaltemperature of 100° C. for 2 hours to complete dissolution. It was thenslowly air-cooled to room temperature and stirred for 21 hours. Theprecipitated hydrochloride was filtered to give 235 mg of the titlecompound as colorless crystals.

¹H-NMR (400 MHz, CD₃OD) δ: 0.96 (s, 6H), 1.03 (t, J=7.2 Hz, 3H), 1.18(s, 6H), 1.18-1.52 (m, 10H), 1.72-1.81 (m, 2H), 3.10-3.75 (m, 8H), 3.56(tt, J=12.4, 2.8 Hz, 1H), 7.13-7.20 (m, 3H), 7.26-7.29 (m, 1H). MS m/e(ESI) 357 (MH⁺).

Example 91-Cyclopropylmethyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

To a solution of 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine(200 mg, 0.666 mmol) prepared in Example (8b) in tetrahydrofuran (4 mL)was added cyclopropanecarbaldehyde (70 mg, 0.999 mmol), and the mixturewas stirred at room temperature for 5 minutes. Sodiumtriacetoxyborohydride (282 mg, 1.33 mmol) was added to the reactionmixture, and after stirring for 5 minutes, acetic acid (0.038 mL, 0.666mmol) was added and the mixture was stirred at room temperature for 2hours.

After the reaction completed, saturated aqueous sodium hydrogencarbonatewas added to the reaction mixture and the mixture was extracted withethyl acetate. The organic layer was dried over anhydrous sodiumsulfate. The desiccant was filtered off and the filtrate wasconcentrated under reduced pressure. The resultant residue was purifiedby NH silica gel column chromatography (ethyl acetate/heptane) to give182 mg of1-cyclopropylmethyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazineas colorless crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 0.12-0.16 (m, 2H), 0.52-0.56 (m, 2H),0.88-0.96 (m, 1H), 0.92 (s, 6H), 1.12 (s, 6H), 1.13-1.45 (m, 6H), 2.32(d, J=6.4 Hz, 2H), 2.70 (brs, 4H), 2.95 (t, J=4.4 Hz, 4H), 3.60 (tt,J=12.4, 2.8 Hz, 1H), 7.04-7.08 (m, 1H), 7.11-7.14 (m, 2H), 7.20-7.22 (m,1H).

The obtained compound (147 mg, 0.415 mmol) was dissolved indichloromethane (3 mL), and then a 4N solution of hydrogen chloride inethyl acetate (0.11 mL, 0.456 mmol) was added to the mixture under anitrogen atmosphere. After stirring for 15 minutes at room temperature,the solvent was distilled off under reduced pressure. Ethyl acetate (13mL) was added to the resultant residue, and the mixture was stirred atan external temperature of 100° C. for 1 hour to complete dissolution.The solution was then air-cooled to room temperature and stirred for 19hours and 45 minutes. The precipitated hydrochloride was filtered togive 134 mg of the title compound as colorless crystals.

MS m/e (ESI) 355 (MH⁺).

Example 102-{4-[2-(4-t-Butylcyclohexyl)phenyl]piperazin-1-yl}-N-ethylacetamidehydrochloride

10a 1-[2-(4-t-Butylcyclohexyl)phenyl]piperazine

To a mixture of 2-(4-t-butylcyclohexyl)phenylamine (810 mg, 3.5 mmol)prepared in Example (2c) and 1,2-dichlorobenzene (5 mL) was addedbis(2-chloroethyl)amine hydrochloride (750 mg, 4.2 mmol), and themixture was heated at reflux for 1 hour and 30 minutes.

The reaction mixture was cooled to room temperature, saturated aqueoussodium hydrogencarbonate was added and the mixture was extracted with amixed solvent of ethyl acetate and tetrahydrofuran. The collectedorganic layer was dried over anhydrous magnesium sulfate. The desiccantwas filtered off and the filtrate was concentrated under reducedpressure. The resultant residue was purified by NH silica gel columnchromatography (ethyl acetate/methanol) to give 420 mg of the titlecompound as a light yellow solid, as a mixture of diastereomers at theposition of t-butylcyclohexyl.

MS m/e (ESI) 301 (MH⁺).

10b 2-{4-[2-(4-t-Butylcyclohexyl)phenyl]piperazin-1-yl}-N-ethylacetamidehydrochloride

A mixture of 1-[2-(4-t-butylcyclohexyl)phenyl]piperazine (400 mg, 1.33mmol) prepared in Example (10a), 2-chloro-N-ethylacetamide (200 mg, 1.65mmol), potassium carbonate (400 mg, 2.89 mmol) and dimethylformamide (15mL) was stirred at an external temperature of 115° C. for 2 hours.

After the reaction, ethyl acetate and water were added to the reactionmixture and the mixture was extracted with ethyl acetate. The collectedorganic layer was washed twice with water and then with brine, and thendried over anhydrous sodium sulfate. The desiccant was filtered off andthe filtrate was concentrated under reduced pressure. The resultantresidue was purified by NH silica gel column chromatography (ethylacetate/hexane) to give 506 mg of2-{4-[2-(4-t-butylcyclohexyl)phenyl]piperazin-1-yl}-N-ethylacetamide asa colorless oil, as a mixture of diastereomers at the position oft-butylcyclohexyl.

¹H-NMR (400 MHz, CDCl₃) δ: 0.88 (s, 9H×0.6), 0.90 (s, 9H×0.4), 1.10-1.21(m, 6H), 1.35-1.48 (m, 2H), 1.68-1.98 (m, 4H), 2.67 (brs, 4H), 2.87-2.92(m, 4H), 3.06 (s, 2H×0.6), 3.09 (s, 2H×0.4), 3.30-3.40 (m, 4H),7.05-7.22 (m, 3H+1H×0.4), 7.44 (d, J=8.0 Hz, 1H×0.6).

The product was dissolved in ethyl acetate, and a 4N solution ofhydrogen chloride in ethyl acetate was added. The solution wasconcentrated under reduced pressure, diethyl ether was added to theresultant residue and the precipitated crystals were filtered. Thecrystals were then dried under reduced pressure to give 476 mg of thetitle compound as colorless crystals, as a mixture of diastereomers atthe position of t-butylcyclohexyl.

MS m/e (ESI) 386 (MH⁺).

Example 112-{4-[2-(4-t-Butylcyclohexyl)phenyl]piperazin-1-yl}-1-(piperidin-1-yl)ethanonehydrochloride

A mixture of 1-[2-(4-t-butylcyclohexyl)phenyl]piperazine (50 mg, 0.166mmol) prepared in Example (10a), 1-(2-chloroacetyl)piperidine (33 mg,0.204 mmol), potassium carbonate (60 mg, 0.434 mmol) anddimethylformamide (5 mL) was stirred at an external temperature of 115°C. for 2 hours.

Ethyl acetate, saturated aqueous ammonium chloride and water were addedto the reaction mixture and the mixture was extracted with ethylacetate. The collected organic layer was washed twice with brine andthen with brine, and then dried over anhydrous sodium sulfate. Thedesiccant was filtered off and the filtrate was concentrated underreduced pressure. The resultant residue was purified by NH silica gelcolumn chromatography (ethyl acetate/hexane) to give 51 mg of2-{4-[2-(4-t-butylcyclohexyl)phenyl]piperazin-1-yl}-1-(piperidin-1-yl)ethanoneas a colorless oil, as a mixture of diastereomers at the position oft-butylcyclohexyl.

¹H-NMR (400 MHz, CDCl₃) δ: 0.88 (s, 9H×0.6), 0.90 (s, 9H×0.4), 1.10-1.27(m, 2H), 1.35-1.46 (m, 2H), 1.54-1.98 (m, 10H), 2.65 (brs, 4H),2.85-2.92 (m, 4H), 2.94-3.04 (m, 1H×0.4), 3.24 (s, 2H×0.6), 3.26 (s,2H×0.4), 3.35-3.47 (m, 1H+1H×0.6), 3.50-3.58 (m, 4H), 7.05-7.28 (m,3H+1H×0.4), 7.40 (d, J=8.0 Hz, 1H×0.6).

The product was dissolved in ethyl acetate, and a 4N solution ofhydrogen chloride in ethyl acetate was added. The solution wasconcentrated, ethyl acetate was added to the resultant residue, and themixture was further concentrated.

Diethyl ether was added to the resultant residue, and the precipitatedcrystals were filtered and dried under reduced pressure to give 37 mg ofthe title compound as colorless crystals, as a mixture of diastereomersat the position of t-butylcyclohexyl.

MS m/e (ESI) 426 (MH⁺).

Example 12cis-4-(4-t-Butylcyclohexyl)-3-(4-butylpiperazine-1-yl)benzonitrilehydrochloride

12a 1-(4-t-Butylcyclohex-1-enyl)-4-methoxy-2-nitrobenzene

A mixture of2-(4-t-butylcyclohex-1-enyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane(3.17 g, 12 mmol) prepared in Example (7d),1-bromo-4-methoxy-2-nitrobenzene (2.32 g, 10 mmol), tripotassiumphosphate (4.8 g, 15 mmol), 1,2-dimethoxyethane (30 mL) and water (5 mL)was stirred at room temperature under a nitrogen atmosphere. To thisreaction mixture was added tetrakis(triphenylphosphine)palladium(0) (578mg, 0.5 mmol). The mixture was stirred at an external temperature of 70°C. for 18 hours and 30 minutes.

Ethyl acetate and water were added to the reaction mixture, which wasthen passed through Celite for filtration. The filtrate was subjected tooil-water distribution and the obtained organic layer was dried overanhydrous sodium sulfate. The desiccant was filtered off and thefiltrate was concentrated under reduced pressure. The resultant residuewas purified by silica gel column chromatography (ethyl acetate/hexane)to give 2.89 g of the title compound as a yellow solid, in racemic format the position of t-butyl.

¹H-NMR (400 MHz, CDCl₃) δ: 0.89 (s, 9H), 1.31-1.43 (m, 2H), 1.86-1.95(m, 2H), 2.13-2.34 (m, 3H), 3.85 (s, 3H), 5.59-5.61 (m, 1H), 7.05 (dd,J=8.8, 2.4 Hz, 1H), 7.17 (d, J=8.8 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H).

12b 2-(4-t-Butylcyclohexyl)-5-methoxyphenylamine

A mixture of 1-(4-t-butylcyclohex-1-enyl)-4-methoxy-2-nitrobenzene (2.89g, 10.0 mmol) prepared in Example (12a), 10% palladium on carbon (1.0 g,wet), methanol (15 mL) and tetrahydrofuran (15 mL) was stirred for 12hours under hydrogen atmosphere at atmospheric pressure and roomtemperature.

The reaction mixture was passed through Celite for filtration, and thefiltrate was concentrated under reduced pressure. The resultant residuewas purified by silica gel column chromatography (ethyl acetate) to give2.56 g of the title compound as a yellow solid, as a mixture ofdiastereomers at the position of t-butylcyclohexyl.

¹H-NMR (400 MHz, CDCl₃) δ: 0.86 (s, 9H×0.65), 0.89 (s, 9H×0.35),1.05-1.46 (m, 4H), 1.58-1.66 (m, 2H×0.65), 1.70-1.81 (m, 2H×0.65),1.88-1.98 (m, 4H×0.35), 2.03-2.10 (m, 1H), 2.34 (tt, J=11.6, 3.2 Hz,1H×0.35), 2.84-2.89 (m, 1H×0.65), 3.65 (brs, 2H), 3.74 (s, 3H×0.35),3.75 (s, 3H×0.65), 6.25-6.26 (m, 1H), 6.32-6.36 (m, 1H), 7.00 (d, J=8.4Hz, 1H×0.35), 7.24 (d, J=8.4 Hz, 1H×0.65).

12c 1-[2-(4-t-Butylcyclohexyl)-5-methoxyphenyl]piperazine

To a solution of 2-(4-t-butylcyclohexyl)-5-methoxyphenylamine (2.56 g,9.79 mmol) prepared in Example (12b) in 1,2-dichlorobenzene (10 mL) wasadded bis(2-chloroethyl)amine hydrochloride (2.10 g, 11.75 mmol), themixture was stirred at an external temperature of 200° C. under anitrogen atmosphere.

During the reaction, a nitrogen stream was blown into the reactor toremove the hydrogen chloride gas in the reactor. This procedure wasrepeated several times.

After 1 hour and 30 minutes, the mixture was air cooled to roomtemperature. Saturated aqueous sodium hydrogencarbonate and ethylacetate were added to the reaction mixture and the mixture was stirred,after which insoluble matters in the reaction mixture were filteredthrough Celite. The filtrate was extracted with ethyl acetate, theobtained organic layer was washed with brine and then dried overanhydrous sodium sulfate. The desiccant was filtered off and thefiltrate was concentrated under reduced pressure. The resultant residuewas purified by NH silica gel column chromatography (ethylacetate/hexane) to give 1.77 g of the title compound as a brown oil, asa mixture of diastereomers at the position of t-butylcyclohexyl.

¹H-NMR (400 MHz, CDCl₃) δ: 0.88 (s, 9H×0.65), 0.89 (s, 9H×0.35),1.09-1.21 (m, 4H), 1.36-1.45 (m, 1H), 1.56-1.63 (m, 1H), 1.68-1.97 (m,4H), 2.77-2.83 (m, 4H), 2.91 (tt, J=12.4, 3.2 Hz, 1H×0.35), 2.98-3.03(m, 4H), 3.32 (tt, J=5.2 Hz, 1H×0.65), 3.77 (s, 3H×0.35), 3.783 (s,3H×0.65), 6.61-6.67 (m, 1H×0.65+2H×0.35), 6.73 (d, J=2.4 Hz, 1H×0.65),7.13 (d, J=8.8 Hz, 1H×0.35), 7.34 (d, J=8.4 Hz, 1H×0.65).

12d 4-(4-t-Butylcyclohexyl)-3-piperazin-1-ylphenol

A mixture of 1-[2-(4-t-butylcyclohexyl)-5-methoxyphenyl]piperazine (1.77g, 5.36 mmol) prepared in Example (12c), 48% hydrobromic acid (50 mL)and acetic acid (30 mL) was stirred at an external temperature of 130°C. for 8 hours and 30 minutes under a nitrogen atmosphere.

The reaction mixture was then cooled in an ice water bath and stirred.The reaction mixture was adjusted to pH 8-9 with 5N aqueous sodiumhydroxide. The precipitated solid was filtered and washed with water,and then a mixed solvent of methanol and ethyl acetate (mixing ratio(v/v)=1/5) was added to the solid. Insoluble matters were filtered offand the filtrate was concentrated under reduced pressure. Diethyl etherwas added to the resultant residue, and then the mixture was sonicatedand the resulting solid was filtered. The solid was dried under reducedpressure to give 1.43 g of the title compound as a light brown solid, asa mixture of diastereomers at the position of t-butylcyclohexyl.

¹H-NMR (400 MHz, DMSO-d₆) δ: 0.85 (s, 9H×0.65), 0.86 (s, 9H×0.35),1.00-1.90 (m, 9H), 2.17 (brs, 1H), 2.59-2.68 (m, 1H×0.35+4H), 2.75-2.83(m, 4H), 3.20-3.25 (m, 1H×0.65), 6.40-6.46 (m, 1H×0.35+1H), 6.52 (d,J=2.8 Hz, 1H×0.65), 6.95 (d, J=8.4 Hz, 1H×0.35), 7.12 (d, J=8.4 Hz,1H×0.65), 9.03 (brs, 1H×0.35), 9.05 (brs, 1H×0.65).

12e 4-(4-t-Butylcyclohexyl)-3-(4-butylpiperazine-1-yl)phenol

In anhydrous tetrahydrofuran (10 mL) was dissolved4-(4-t-butylcyclohexyl)-3-piperazin-1-ylphenol (1 g, 3.16 mmol) preparedin Example (12d), and the solution was cooled in an ice water bath undera nitrogen atmosphere. To the reaction mixture were added butyraldehyde(0.31 mL, 3.48 mmol), sodium triacetoxyborohydride (1 g, 4.74 mmol) andacetic acid (0.18 mL, 3.16 mmol) in that order, and the mixture waswarmed to room temperature with stirring.

The mixture was then stirred for 4 hours and 30 minutes, and saturatedaqueous sodium hydrogencarbonate was added to the reaction mixture toquench the reaction. Ethyl acetate and water were further added, and theresulting reaction mixture was transferred to a separatory funnel andvigorously shaken, and then allowed to stand. The separated aqueouslayer was removed and the organic layer was washed with water and brinein that order and then dried over anhydrous sodium sulfate. Thedesiccant was filtered off and then the filtrate was concentrated underreduced pressure. The resultant residue was purified by NH silica gelcolumn chromatography (ethyl acetate/hexane) to give 886 mg of the titlecompound as colorless crystals, as a mixture of diastereomers at theposition of t-butylcyclohexyl.

¹H-NMR (400 MHz, CDCl₃) δ: 0.88 (s, 9H×0.7), 0.89 (s, 9H×0.3), 0.94 (t,J=7.6 Hz, 3H), 1.01-1.96 (m, 13H), 2.42-2.92 (m, 1H×0.3+10H), 3.28 (tt,J=5.2, 5.2 Hz, 1H×0.7), 6.53-6.59 (m, 1H), 6.65 (d, J=2.8 Hz, 1H×0.3),6.71 (d, J=2.8 Hz, 1H×0.7), 7.06 (d, J=8.4 Hz, 1H×0.3), 7.27 (d, J=8.4Hz, 1H×0.7).

The 1H of OH could not be identified.

12f Trifluoromethanesulfonic acidcis-4-(4-t-butylcyclohexyl)-3-(4-butylpiperazin-1-yl)phenyl ester andTrifluoromethanesulfonic acidtrans-4-(4-t-butylcyclohexyl)-3-(4-butylpiperazine-1-yl)phenyl ester

A solution of 4-(4-t-butylcyclohexyl)-3-(4-butylpiperazine-1-yl)phenol(1.6 g, 4.29 mmol) prepared in Example (12e) and triethylamine (3.1 mL,22.24 mmol) in anhydrous dichloromethane (30 mL) was cooled in anice-ethanol bath. Trifluoromethanesulfonic anhydride (1.1 mL, 6.54 mmol)was gradually added dropwise to the solution over 30 minutes withstirring.

After stirring for 30 minutes, ethyl acetate, saturated aqueous ammoniumchloride and water were added to the reaction mixture and the mixturewas extracted with ethyl acetate. The collected organic layer was washedwith brine and then dried over anhydrous sodium sulfate. The desiccantwas filtered off and the filtrate was concentrated under reducedpressure. The resultant residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give 946 mg oftrifluoromethanesulfonic acidcis-4-(4-t-butylcyclohexyl)-3-(4-butylpiperazine-1-yl)phenyl ester, 110mg of trifluoromethanesulfonic acidtrans-4-(4-t-butylcyclohexyl)-3-(4-butylpiperazine-1-yl)phenyl ester and946 mg of a cis/trans mixture, each as a colorless oil. The cis/transmixture was further purified by silica gel column chromatography (ethylacetate/hexane) to give 214 mg of trifluoromethanesulfonic acidcis-4-(4-t-butylcyclohexyl)-3-(4-butylpiperazine-1-yl)phenyl ester, 82mg of trifluoromethanesulfonic acidtrans-4-(4-t-butylcyclohexyl)-3-(4-butylpiperazine-1-yl)phenyl ester and434 mg of a cis/trans mixture, each as a colorless oil.

cis form: ¹H-NMR (400 MHz, CDCl₃) δ: 0.89 (s, 9H), 0.94 (t, J=7.2 Hz,3H), 1.15-1.45 (m, 6H), 1.47-1.67 (m, 3H), 1.67-1.80 (m, 2H), 1.86-1.95(m, 2H), 2.37-2.44 (m, 2H), 2.59 (brs, 4H), 2.88 (t, J=4.8 Hz, 4H), 3.35(tt, J=5.2, 5.2 Hz, 1H), 6.97 (dd, J=8.4, 2.8 Hz, 1H), 7.00 (d, J=2.8Hz, 1H), 7.45 (d, J=8.4 Hz, 1H).

trans form: ¹H-NMR (400 MHz, CDCl₃) δ: 0.90 (s, 9H), 0.95 (t, J=7.2 Hz,3H), 1.08-1.20 (m, 2H), 1.32-1.46 (m, 4H), 1.48-1.62 (m, 3H), 1.78-1.94(m, 4H), 2.40-2.46 (m, 2H), 2.62 (brs, 4H), 2.89 (t, J=4.8 Hz, 4H), 2.94(tt, J=12.0, 3.6 Hz, 1H), 6.94 (d, J=2.4 Hz, 1H), 6.95 (dd, J=9.2, 2.4Hz, 11H), 7.24 (d, J=9.2 Hz, 1H).

12g cis-4-(4-t-Butylcyclohexyl)-3-(4-butylpiperazine-1-yl)benzonitrilehydrochloride

A mixture of trifluoromethanesulfonic acidcis-4-(4-t-butylcyclohexyl)-3-(4-butylpiperazine-1-yl)phenyl ester (1.16g, 2.3 mmol) prepared in Example (12f), zinc cyanide (2.7 g, 23 mmol)and dimethylformamide (30 mL) was stirred at room temperature under anitrogen atmosphere. Tetrakis(triphenylphosphine)palladium(0) (370 mg,0.32 mmol) was added to this mixture. The mixture was then stirred at anexternal temperature of 100° C. for 19 hours and 10 minutes.

Ethyl acetate, dilute aqueous ammonia and water were added to thereaction mixture and the mixture was extracted with ethyl acetate. Thecollected organic layer was washed with dilute aqueous ammonia, waterand brine in that order and then dried over anhydrous sodium sulfate.The desiccant was filtered off and the filtrate was concentrated underreduced pressure. The resultant residue was purified by NH silica gelcolumn chromatography (ethyl acetate/hexane) to give 880 mg ofcis-4-(4-t-butylcyclohexyl)-3-(4-butylpiperazine-1-yl)benzonitrile as acolorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.88 (s, 9H), 0.94 (t, J=7.2 Hz, 3H),1.15-1.44 (m, 6H), 1.48-1.67 (m, 3H), 1.70-1.80 (m, 2H), 1.88-1.96 (m,2H), 2.38-2.44 (m, 2H), 2.59 (brs, 4H), 2.88 (t, J=4.8 Hz, 4H), 3.38(tt, J=5.6, 5.6 Hz, 1H), 7.34 (dd, J=7.6, 2.0 Hz, 1H), 7.35 (d, J=2.0Hz, 1H), 7.47 (d, J=7.6 Hz, 1H).

The product was dissolved in ethyl acetate, and a 4N solution ofhydrogen chloride in ethyl acetate was added. The solution wasconcentrated, diethyl ether and hexane were added to the resultantresidue, and the precipitated crystals were filtered. The crystals werethen dried under reduced pressure to give 892 mg of the title compoundas colorless crystals.

MS m/e (ESI) 382 (MH⁺).

Example 13trans-4-(4-t-Butylcyclohexyl)-3-(4-butylpiperazin-1-yl)benzonitrilehydrochloride

A mixture of trifluoromethanesulfonic acidtrans-4-(4-t-butylcyclohexyl)-3-(4-butylpiperazine-1-yl)phenyl ester (30mg, 0.0594 mmol) prepared in Example (12f), zinc cyanide (8 mg, 0.0681mmol) and dimethylformamide (1 mL) was stirred at room temperature undera nitrogen atmosphere. Tetrakis(triphenylphosphine)palladium(0) (6 mg,0.0052 mmol) was added to the mixture. The mixture was then stirred atan external temperature of 100° C. for 9 hours. Zinc cyanide (70 mg,0.596 mmol) and tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.0173mmol) were further added to the reaction mixture, which was then stirredat an external temperature of 100° C. for 14 hours and 10 minutes.

After the reaction, ethyl acetate, dilute aqueous ammonia and water wereadded to the reaction mixture and the mixture was extracted with ethylacetate. The collected organic layer was washed with dilute aqueousammonia, water and brine in that order and then dried over anhydroussodium sulfate. The desiccant was filtered off and the filtrate wasconcentrated under reduced pressure. The resultant residue was purifiedby NH silica gel column chromatography (ethyl acetate/hexane) to give 10mg oftrans-4-(4-t-butylcyclohexyl)-3-(4-butylpiperazine-1-yl)benzonitrile asa light yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.90 (s, 9H), 0.95 (t, J=7.2 Hz, 3H),1.09-1.20 (m, 2H), 1.31-1.46 (m, 4H), 1.49-1.58 (m, 3H), 1.77-1.96 (m,4H), 2.40-2.46 (m, 2H), 2.62 (brs, 4H), 2.89 (t, J=5.2 Hz, 4H), 2.99(tt, J=12.0, 3.2 Hz, 1H), 7.27 (d, J=7.6 Hz, 1H), 7.30 (d, J=1.6 Hz,1H), 7.32 (dd, J=7.6, 1.6 Hz, 1H).

The product was dissolved in ethyl acetate, and a 4N solution ofhydrogen chloride in ethyl acetate was added. The solution wasconcentrated, diethyl ether and hexane were added to the resultantresidue to solidify, and it was then triturated by sonication. Afterremoving the supernatant, the resultant residual solid was dried underreduced pressure to give 7 mg of the title compound as a white solid.

MS m/e (ESI) 382 (MH⁺).

Example 14 1-Butyl-4-(2-cyclohexylphenyl)piperazine hydrochloride

Trifluoromethanesulfonic acid cyclohex-1-enyl ester

Reference: Crich, D.; Smith, M.; Yao, Q.; Picione, J.; Synthesis 2001,(2), 323-326.

14a 2-(Cyclohex-1-enyl)nitrobenzene

Trifluoromethanesulfonic acid cyclohex-1-enyl ester (1.0 g, 5.9 mmol)was used as the starting material instead of trifluoromethanesulfonicacid 4-t-butylcyclohex-1-enyl ester for reaction in a manner similar toExample (2b) and treated in a similar manner to give 0.56 g of the titlecompound as a red oil.

14b 2-Cyclohexylphenylamine

2-(Cyclohex-1-enyl)nitrobenzene (0.56 g, 2.75 mmol) prepared in Example(14a) was reacted and treated in a manner similar to Example (2c) togive 0.51 g of the title compound as a light yellow oil.

14c 1-(2-Cyclohexylphenyl)piperazine

2-Cyclohexylphenylamine (0.48 g, 2.75 mmol) prepared in Example (14b)was reacted and treated in a manner similar to Example (3c) to give 0.25g of the title compound as a light yellow oil.

14d 1-Butyl-4-(2-cyclohexylphenyl)piperazine hydrochloride

1-(2-Cyclohexylphenyl)piperazine (0.25 g, 1.02 mmol) prepared in Example(14c) was used as the starting material, and butyraldehyde was usedinstead of tetrahydropyran-4-carbaldehyde for the reaction and treatmentin a manner similar to Example (6g) to give 195 mg of the title compoundas a light yellow solid.

MS m/e (ESI) 301 (MH⁺).

Example 15 1-Butyl-4-[2-(4-t-butylcyclohexyl)phenyl]piperazinehydrochloride

1-[2-(4-t-Butylcyclohexyl)phenyl]piperazine (160 mg, 0.53 mmol) preparedin Example (10a) was used as the starting material.

Reaction and treatment were carried out in a manner similar to Example(6g) using butyraldehyde instead of tetrahydropyran-4-carbaldehyde, togive 65 mg of the title compound as colorless crystals, as a mixture ofdiastereomers at the position of t-butylcyclohexyl.

MS m/e (ESI) 357 (MH⁺).

Example 164-Butyl-1-[2-(4-t-butylcyclohexyl)phenyl]-3-methylpiperazin-2-onehydrochloride

16aN-[2-(4-t-Butylcyclohexyl)phenyl]-2-chloro-N-(2-hydroxyethyl)propionamide

2-[2-(4-t-Butylcyclohexyl)phenylamino]ethanol (271 mg, 0.984 mmol)prepared in Example (2d) was used as the starting material.

2-Chloropropionylchloride was used instead of chloroacetyl chloride forreaction in a manner similar to Example (2e) and treated in a similarmanner, to give 136 mg of the title compound as a colorless oil, as amixture of diastereomers at the position of t-butylcyclohexyl andmethyl.

16bN-[2-(4-t-Butylcyclohexyl)phenyl]-2-chloro-N-(2-oxoethyl)propionamide

N-[2-(4-t-Butylcyclohexyl)phenyl]-2-chloro-N-(2-hydroxyethyl)propionamide(134 mg, 0.366 mmol) prepared in Example (16a) was used as the startingmaterial.

This was reacted and treated in a manner similar to Example (2f) to givea crude product of the title compound (166 mg) as a light yellow oil, asa mixture of diastereomers at the position of t-butylcyclohexyl andmethyl.

16c 4-Butyl-1-[2-(4-t-butylcyclohexyl)phenyl]-3-methylpiperazin-2-onehydrochloride

N-[2-(4-t-Butylcyclohexyl)phenyl]-2-chloro-N-(2-oxoethyl)propionamide(165 mg) prepared in Example (16b) was used as the starting material.

This was reacted and treated in a manner similar to Example (2g) to give80 mg of4-butyl-1-[2-(4-t-butylcyclohexyl)phenyl]-3-methylpiperazin-2-one as alight yellow oil, as a mixture of diastereomers at the position oft-butylcyclohexyl and methyl.

The product was converted to a hydrochloride by a method similar toExample (2g) to give 51 mg of the title compound as a light brown solid,as a mixture of diastereomers at the position of t-butylcyclohexyl andmethyl.

MS m/e (ESI) 385 (MH⁺).

Example 171-{4-[2-(4,4-Dimethylcyclohexyl)phenyl]piperazin-1-yl}butan-2-onehydrochloride

1-[2-(4,4-Dimethylcyclohexyl)phenyl]piperazine (420 mg, 1.54 mmol)prepared in Example (3c) was used as the starting material.

1-Bromo-2-butanone was used instead of 2-chloro-N-ethylacetamide andacetonitrile was used instead of dimethylformamide, for reaction in amanner similar to Example (10b) and treated in a similar manner to give488 mg of1-{4-[2-(4,4-dimethylcyclohexyl)phenyl]piperazin-1-yl}butan-2-one as ayellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.97 (s, 3H), 1.01 (s, 3H), 1.10 (t, J=7.2Hz, 3H), 1.29-1.36 (m, 2H), 1.46-1.68 (m, 6H), 2.51 (q, J=7.2 Hz, 2H),2.58-2.72 (br, 4H), 2.90-3.00 (m, 5H), 3.28 (s, 2H), 7.06-7.18 (m, 3H),7.25-7.28 (m, 1H).

The oil was dissolved in dichloromethane, and a 4N solution of hydrogenchloride in ethyl acetate was added. The solution was diluted withhexane and concentrated under reduced pressure. To the resultant solidresidue was added diethyl ether-hexane, it was triturated by sonicationand then filtered to give 496 mg of the title compound as colorlesscrystals.

MS m/e (ESI) 343 (MH⁺).

Example 184-[3-(4-t-Butylcyclohex-1-enyl)-4-(4-butylpiperazine-1-yl)phenyl]morpholinehydrochloride

18a Trifluoromethanesulfonic acid 5-morpholin-4-yl-2-nitrophenyl ester

Reaction and treatment were carried out in a manner similar to Example(7c), using 5-morpholin-4-yl-2-nitrophenol (12 g, 53.5 mmol) as thestarting material instead of 5-(4-methoxypiperidin-1-yl)-2-nitrophenol,and using pyridine instead of the dichloromethane-triethylamine solvent,to give 17.24 g of the title compound as yellow crystals.

18b 4-[3-(4-t-Butylcyclohex-1-enyl)-4-nitrophenyl]morpholine

The trifluoromethanesulfonic acid 5-morpholin-4-yl-2-nitrophenyl ester(3.08 g, 8.64 mmol) prepared in Example (18a) was used as the startingmaterial for reaction in a manner similar to Example (7e) and treated ina similar manner. Consequently, 2.68 g of the title compound wasobtained as yellow crystals, in racemic form at the position of t-butyl.

18c 2-(4-t-Butylcyclohex-1-enyl)-4-morpholin-4-yl)phenylamine

4-[3-(4-t-butylcyclohex-1-enyl)-4-nitrophenyl]morpholine (2.68 g, 7.77mmol) prepared in Example (18b) was used as the starting material forreaction in a manner similar to Example (6e) and treated in a similarmanner. Consequently, 2.19 g of the title compound was obtained as lightbrown crystals, in racemic form at the position of t-butyl.

18d 4-[3-(4-t-Butylcyclohex-1-enyl)-4-piperazin-1-ylphenyl]morpholine

Reaction was conducted in a manner similar to Example (7g) at 200° C.for 18 hours, using the2-(4-t-butylcyclohex-1-enyl)-4-morpholin-4-yl)phenylamine (2.19 g, 6.96mmol) prepared in Example (18c) as the starting material, and thentreatment was carried out in a similar manner. As a result there wasobtained 1.84 g of the title compound as light brown crystals, inracemic form at the position of t-butyl.

18e4-[3-(4-t-Butylcyclohex-1-enyl)-4-(4-butylpiperazin-1-yl)phenyl]morpholinehydrochloride

Reaction and treatment were carried out in a manner similar to Example(7h), using4-[3-(4-t-butylcyclohex-1-enyl)-4-piperazin-1-ylphenyl]morpholine (0.32g, 0.834 mmol) prepared in Example (18d) as the starting material.Consequently, 350 mg of the title compound was obtained as colorlesscrystals, in racemic form at the position of t-butyl.

MS m/e (ESI) 440 (MH⁺).

Example 191-[2-(4-t-Butylcyclohexyl)phenyl]-4-(2-methoxyethyl)piperazinehydrochloride

1-[2-(4-t-Butylcyclohexyl)phenyl]piperazine (100 mg, 0.333 mmol)prepared in Example (10a) was used as the starting material.

Reaction and treatment were carried out in a manner similar to Example(10b) using 2-bromoethylmethyl ether instead of2-chloro-N-ethylacetamide, and acetonitrile instead ofdimethylformamide, to give 115 mg of1-[2-(4-t-butylcyclohexyl)phenyl]-4-(2-methoxyethyl)piperazine as acolorless oil, as a mixture of diastereomers at the position oft-butylcyclohexyl.

The oil was converted to a hydrochloride by a method similar to Example(10b) to give 124 mg of the title compound as colorless crystals, as amixture of diastereomers at the position of t-butylcyclohexyl.

MS m/e (ESI) 359 (MH⁺).

Example 201-[2-(4-t-Butylcyclohex-1-enyl)-4-(4-methoxypiperidin-1-yl)phenyl]-4-cyclopropylmethylpiperazinehydrochloride

1-[2-(4-t-Butylcyclohex-1-enyl)-4-(4-methoxypiperidin-1-yl)phenyl]piperazine(100 mg, 0.243 mmol) prepared in Example (7g) was used as the startingmaterial for reaction in a manner similar to Example (9) and treated ina similar manner, to give 104 mg of1-[2-(4-t-butylcyclohex-1-enyl)-4-(4-methoxypiperidin-1-yl)phenyl]-4-cyclopropylmethylpiperazineas a colorless solid, in racemic form at the position oft-butylcyclohexyl. The product was converted to a hydrochloride by amethod similar to Example (9) to give 79 mg of the title compound as alight yellow solid, in racemic form at the position of t-butyl.

MS m/e (ESI) 466 (MH⁺).

Example 211-Butyl-4-[2-(4,4-dimethylcyclohexyl)-4-(4-ethoxypiperidin-1-yl)phenyl]piperazinehydrochloride

21a 4-Ethoxypiperidine hydrochloride

4-Hydroxypiperidine-1-carboxylic acid t-butyl ester (2.2 g, 10.9 mmol)was used as the starting material.

Ethyl iodide was used instead of methyl iodide for reaction in a mannersimilar to Example (7a) and treated in a similar manner, to give 1.3 gof the title compound as light yellow crystals.

21b 1-Butyl-4-[2-(4,4-dimethylcyclohexyl)phenyl]piperazine hydrochloride

1-[2-(4,4-Dimethylcyclohexyl)phenyl]piperazine (65 mg, 0.239 mmol)prepared in Example (3c) was used as the starting material.

Reaction and treatment were carried out in a manner similar to Example(8c), to give 82 mg of the title compound as colorless crystals.

MS m/e (ESI) 329 (MH⁺).

21c 1-[4-Bromo-2-(4,4-dimethylcyclohexyl)phenyl]-4-butylpiperazine

1-Butyl-4-[2-(4,4-dimethylcyclohexyl)phenyl]piperazine hydrochloride (64mg, 0.175 mmol) prepared in Example (21b) was used as the startingmaterial.

Reaction and treatment were carried out in a manner similar to Example(3e), excluding sodium acetate from the reagents used, to give 71 mg ofthe title compound as a light yellow oil.

21d1-Butyl-4-[2-(4,4-dimethylcyclohexyl)-4-(4-ethoxypiperidin-1-yl)phenyl]piperazinehydrochloride

1-[4-Bromo-2-(4,4-dimethylcyclohexyl)phenyl]-4-butylpiperazine (20 mg,0.0491 mmol) prepared in Example (21c) and 4-ethoxypiperidinehydrochloride (11 mg, 0.0638 mmol) prepared in Example (21a) were usedas the starting materials.

Reaction and treatment were carried out in a manner similar to Example(3f), with further addition of sodium t-butoxide in an equivalent withrespect to 4-ethoxypiperidine hydrochloride, to give1-butyl-4-[2-(4,4-dimethylcyclohexyl)-4-(4-ethoxypiperidin-1-yl)phenyl]piperazineas a colorless oil.

The obtained oil was dissolved in ethyl acetate (3 mL), and then a 4Nsolution of hydrogen chloride in ethyl acetate (0.0082 mL) was added.The mixture was further diluted with hexane (5 mL) and concentratedunder reduced pressure. The crude crystal product precipitated waswashed with hexane and then dried to give 16 mg of the title compound ascolorless crystals.

MS m/e (ESI) 456 (MH⁺).

Example 221-(Tetrahydropyran-4-ylmethyl)-4-[2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazinehydrochloride

1-[2-(3,3,5,5-Tetramethylcyclohex-1-enyl)phenyl]piperazine (120 mg,0.402 mmol) prepared in Example (4f) was used as the starting material.

Tetrahydropyran-4-carbaldehyde was used instead of butyraldehyde forreaction in a manner similar to Example (4g) and treated in a similarmanner, to give 131 mg of1-(tetrahydropyran-4-ylmethyl)-4-[2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazineas a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.02 (s, 6H), 1.07 (s, 6H), 1.23-1.34 (m,2H), 1.39 (s, 2H), 1.67-1.83 (m, 3H), 2.17 (d, J=1.6 Hz, 2H), 2.22 (d,J=6.8 Hz, 2H), 2.51 (brs, 4H), 2.99 (brs, 4H), 3.39 (td, J=12.0, 2.0 Hz,2H), 3.95-3.99 (m, 2H), 5.50 (s, 1H), 6.96-7.00 (m, 2H), 7.07 (dd,J=7.6, 1.6 Hz, 1H), 7.18 (ddd, J=8.0, 8.0, 2.0 Hz, 1H).

This was converted to a hydrochloride by a method similar to Example(4g) to give 113 mg of the title compound as colorless crystals.

MS m/e (ESI) 397 (MH⁺).

Example 231-{4-[2-(3,3,5,5-Tetramethylcyclohex-1-enyl)phenyl]piperazin-1-yl}butan-2-onehydrochloride

1-[2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazine (40 mg, 0.134mmol) prepared in Example (4f) was used as the starting material.

1-Bromo-2-butanone was used instead of 2-chloro-N-ethylacetamide andacetonitrile was used instead of dimethylformamide for reaction in amanner similar to Example (10b) and treated in a similar manner, to give31 mg of1-{4-[2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazin-1-yl}butan-2-oneas a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.02 (s, 6H), 1.06 (s, 6H), 1.08 (t, J=7.6Hz, 3H), 1.39 (s, 2H), 2.16 (d, J=1.6 Hz, 2H), 2.49 (q, J=7.6 Hz, 2H),2.59 (brs, 4H), 3.05 (t, J=4.8 Hz, 4H), 3.23 (s, 2H), 5.50 (t, J=1.6 Hz,1H), 6.97-7.02 (m, 2H), 7.07 (dd, J=8.0, 1.6 Hz, 1H), 7.19 (ddd, J=8.0,8.0, 1.6 Hz, 1H).

This was converted to a hydrochloride by a method similar to Example(4g) to give 38 mg of the title compound as a light brown solid.

MS m/e (ESI) 369 (MH⁺).

Example 241-(2-Methoxyethyl)-4-[2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazinehydrochloride

1-[2-(3,3,5,5-Tetramethylcyclohex-1-enyl)phenyl]piperazine (40 mg, 0.134mmol) prepared in Example (4f) was used as the starting material.

2-Bromoethylmethyl ether was used instead of 2-chloro-N-ethylacetamideand acetonitrile was used instead of dimethylformamide for reaction in amanner similar to Example (10b) and treated in a similar manner, to give31 mg of1-(2-methoxyethyl)-4-[2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazine.

¹H-NMR (400 MHz, CDCl₃) δ: 1.02 (s, 6H), 1.07 (s, 6H), 1.39 (s, 2H),2.17 (d, J=1.2 Hz, 2H), 2.61 (brs, 4H), 2.62 (t, J=5.6 Hz, 2H), 3.03 (t,J=4.4 Hz, 4H), 3.37 (s, 3H), 3.55 (t, J=5.6 Hz, 2H), 5.50 (t, J=1.6 Hz,1H), 6.96-7.02 (m, 2H), 7.07 (dd, J=7.6, 2.0 Hz, 1H), 7.18 (ddd, J=8.0,8.0, 2.0 Hz, 1H).

This was converted to a hydrochloride by a method similar to Example(4g) to give 31 mg of the title compound as colorless crystals.

MS m/e (ESI) 357 (MH⁺).

Example 251-{4-[2-(3,3,5,5-Tetramethylcyclohexyl)phenyl]piperazin-1-yl}butan-2-onehydrochloride

1-[2-(3,3,5,5-Tetramethylcyclohexyl)phenyl]piperazine (40 mg, 0.133mmol) prepared in Example (8b) was used as the starting material.

1-Bromo-2-butanone was used instead of 2-chloro-N-ethylacetamide andacetonitrile was used instead of dimethylformamide for reaction in amanner similar to Example (10b) and treated in a similar manner, to give33 mg of1-{4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazin-1-yl}butan-2-oneas a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.92 (s, 6H), 1.09 (t, J=7.2 Hz, 3H), 1.11(s, 6H), 1.17-1.34 (m, 4H), 1.40-1.44 (m, 2H), 2.50 (q, J=7.2 Hz, 2H),2.66 (brs, 4H), 2.96 (t, J=4.4 Hz, 4H), 3.27 (s, 2H), 3.55 (tt, J=12.8,2.8 Hz, 1H), 7.06-7.11 (m, 1H), 7.13-7.17 (m, 2H), 7.22 (dd, J=8.0, 1.6Hz, 1H).

This was converted to a hydrochloride by a method similar to Example(4g) to give 33 mg of the title compound as a light brown solid.

MS m/e (ESI) 371 (MH⁺).

Example 261-(2-Methoxyethyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

1-[2-(3,3,5,5-Tetramethylcyclohexyl)phenyl]piperazine (40 mg, 0.133mmol) prepared in Example (8b) was used as the starting material.

2-Bromoethyl methyl ether was used instead of 2-chloro-N-ethylacetamideand acetonitrile was used instead of dimethylformamide for reaction in amanner similar to Example (10b) and treated in a similar manner, to give37 mg of1-(2-methoxyethyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine.

¹H-NMR (400 MHz, CDCl₃) δ: 0.92 (s, 6H), 1.12 (s, 6H), 1.17-1.34 (m,4H), 1.41-1.45 (m, 2H), 2.65 (t, J=5.6 Hz, 2H), 2.66 (brs, 4H), 2.95 (t,J=4.4 Hz, 4H), 3.37 (s, 3H), 3.51-3.62 (m, 3H), 7.05-7.11 (m, 1H),7.12-7.17 (m, 2H), 7.22 (dd, J=7.6, 1.6 Hz, 1H).

This was converted to a hydrochloride by a method similar to Example(4g) to give 38 mg of the title compound as colorless crystals.

MS m/e (ESI) 359 (MH⁺).

Example 271-Butyl-4-[5-methoxy-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

27a 4-Methoxy-2-nitro-1-(3,3,5,5-tetramethylcyclohex-1-enyl)benzene

4,4,5,5-Tetramethyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)-[1,3,2]dioxaborolane(2.7 g, 10.3 mmol) prepared in Example (4b) was used instead of2-(4,4-diethylcyclohex-1-enyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolanefor reaction in a manner similar to Example (6d) and treated in asimilar manner, to give 2.5 g of the title compound as a yellow oil.

27b 5-Methoxy-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenylamine

4-Methoxy-2-nitro-1-(3,3,5,5-tetramethylcyclohex-1-enyl)benzene (2.5 g,8.6 mmol) prepared in Example (27a) was reacted and treated in a mannersimilar to Example (6e), to give 2.2 g of the title compound as a yellowoil.

27c 1-[5-Methoxy-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazine

5-Methoxy-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenylamine (2.2 g, 8.6mmol) prepared in Example (27b) was reacted and treated in a mannersimilar to Example (6f), to give 2.0 g of the title compound as a yellowsolid.

27d1-Butyl-4-[5-methoxy-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazinehydrochloride

1-[5-Methoxy-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazine(115 mg, 0.35 mmol) prepared in Example (27c) was reacted and treated ina manner similar to Example (6g), using butyraldehyde instead oftetrahydropyran-4-carbaldehyde, to give 80 mg of the title compound as alight yellow oil.

27e1-Butyl-4-[5-methoxy-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

1-Butyl-4-[5-methoxy-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazinehydrochloride (70 mg, 0.16 mmol) prepared in Example (27d) was reactedand treated in a manner similar to Example (6h), to give 5 mg of thetitle compound as a light yellow solid.

MS m/e (ESI) 387 (MH⁺).

Example 284-[4-(4-Propylpiperazin-1-yl)-3-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]morpholinehydrochloride

28a 5-Morpholin-4-yl-2-nitrophenol

Commercially available 5-fluoro-2-nitrophenol (10 g, 63.65 mmol) wasused as the starting material.

Morpholine was used instead of 4-methoxypiperidine hydrochloride, forreaction in a manner similar to Example (7b). Water was added to thereaction mixture, and then the precipitated crystals were filtered,washed with water and hexane and air-dried to give 14.04 g of the titlecompound as yellow crystals.

28b Trifluoromethanesulfonic acid 5-morpholin-4-yl-2-nitrophenyl ester

5-Morpholin-4-yl-2-nitrophenol (14.04 g, 62.63 mmol) prepared in Example(28a) was used as the starting material.

Reaction and treatment were carried out in a manner similar to Example(7c), to give 21.46 g of the title compound as yellow crystals.

28c 4-[4-Nitro-3-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]morpholine

The trifluoromethanesulfonic acid 5-morpholin-4-yl-2-nitrophenyl ester(2 g, 5.6 mmol) prepared in Example (28b) was used as the startingmaterial.

4,4,5,5-Tetramethyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)-[1,3,2]dioxaborolaneprepared in Example (4b) was used instead of2-(4-t-butylcyclohex-1-enyl)-(4,4,5,5-tetramethyl)-[1,3,2]dioxaborolane,and a mixed solvent of 1,2-dimethoxyethane-water was used as thesolvent, for reaction in a manner similar to Example (7e) and treated ina similar manner, to give 1.7 g of the title compound as a yellow oil.

28d 4-Morpholin-4-yl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenylamine

4-[4-Nitro-3-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]morpholine (1 g,2.9 mmol) prepared in Example (28c) was used as the starting material.

The reaction time was changed to 15 hours and 40 minutes, for reactionin a similar manner and treatment in a manner similar to Example (6e),to give 912 mg of the title compound as a yellow oil.

28e4-[4-piperazin-1-yl-3-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]morpholine

4-Morpholin-4-yl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenylamine (910mg, 2.89 mmol) prepared in Example (28d) was used as the startingmaterial.

This was reacted and treated in a manner similar to Example (7g), togive 820 mg of the title compound as a light brown solid.

28f4-[4-(4-Propylpiperazin-1-yl)-3-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]morpholinehydrochloride

4-[4-piperazin-1-yl-3-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]morpholine(120 mg, 0.313 mmol) prepared in Example (28e) was used as the startingmaterial.

Propionaldehyde was used instead of butyraldehyde for reaction in amanner similar to Example (4g) and treated in a similar manner, to give119 mg of4-[4-(4-propylpiperazin-1-yl)-3-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]morpholineas a white solid.

This was converted to a hydrochloride by a method similar to Example(4g) to give 135 mg of the title compound as a white solid.

MS m/e (ESI) 426 (MH⁺).

Example 294-[3-(4,4-Diethylcyclohex-1-enyl)-4-(4-pentylpiperazin-1-yl)phenyl]morpholinehydrochloride

29a 4-[3-(4,4-Diethylcyclohex-1-enyl)-4-nitrophenyl]morpholine

Trifluoromethanesulfonic acid 5-morpholin-4-yl-2-nitrophenyl ester (3 g,8.42 mmol) prepared in Example (28b) was used as the starting material.

2-(4,4-Diethylcyclohex-1-enyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolaneprepared in Example (6c) was used instead of2-(4-t-butyl-1-cyclohex-1-enyl)-(4,4,5,5-tetramethyl)[1,3,2]dioxaborolane,and a mixed solvent of 1,2-dimethoxyethane-water was used as thesolvent, for reaction in a manner similar to Example (7e) and treated ina similar manner, to give 3.11 g of the title compound as a yellow oil.

29b 2-(4,4-Diethylcyclohex-1-enyl)-4-morpholin-4-ylphenylamine

4-[3-(4,4-Diethylcyclohex-1-enyl)-4-nitrophenyl]morpholine (3.11 g, 9.03mmol) prepared in Example (29a) was used as the starting material.

This was reacted and treated in a manner similar to Example (6e), togive 2.55 g of the title compound as a brown oil.

29c 4-[3-(4,4-Diethylcyclohex-1-enyl)-4-piperazin-1-ylphenyl]morpholine

2-(4,4-Diethylcyclohex-1-enyl)-4-morpholin-4-ylphenylamine (2.55 g, 8.11mmol) prepared in Example (29b) was used as the starting material.

This was reacted and treated in a manner similar to Example (7g), togive 2.01 g of the title compound as a light brown solid.

29d4-[3-(4,4-Diethylcyclohex-1-enyl)-4-(4-pentylpiperazin-1-yl)phenyl]morpholinehydrochloride

4-[3-(4,4-Diethylcyclohex-1-enyl)-4-piperazin-1-ylphenyl]morpholine (30mg, 0.0782 mmol) prepared in Example (29c) was used as the startingmaterial.

This was reacted and treated in a manner similar to Example (1f). Theproduct was further converted to a hydrochloride by a method similar toExample (1f) to give 38.9 mg of the title compound as a white solid.

MS m/e (ESI) 454 (MH⁺).

Example 301-{4-[2-(4,4-Diethylcyclohex-1-enyl)-4-morpholin-4-ylphenyl]piperazin-1-yl}butan-2-onehydrochloride

4-[3-(4,4-Diethylcyclohex-1-enyl)-4-piperazin-1-ylphenyl]morpholine (250mg, 0.652 mmol) prepared in Example (29c) was used as the startingmaterial.

1-Bromo-2-butanone was used instead of 2-chloro-N-ethylacetamide forreaction in a manner similar to Example (10b) and treated in a similarmanner. The product was further converted to a hydrochloride by a methodsimilar to Example (4g) to give 320 mg of the title compound as a whitesolid.

MS m/e (ESI) 454 (MH⁺).

Example 311-Propyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

1-[2-(3,3,5,5-Tetramethylcyclohexyl)phenyl]piperazine (120 mg, 0.399mmol) prepared in Example (8b) was used as the starting material.

Propionaldehyde was used instead of butyraldehyde for reaction in amanner similar to Example (4g) and treated in a similar manner, to give104 mg of 1-propyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazineas a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.92 (s, 6H), 0.93 (t, J=7.2 Hz, 3H), 1.13(s, 6H), 1.16-1.35 (m, 4H), 1.40-1.46 (m, 2H), 1.51-1.60 (m, 2H),2.35-2.39 (m, 2H), 2.61 (brs, 4H), 2.93 (t, J=4.8 Hz, 4H), 3.57 (tt,J=12.8, 2.8 Hz, 1H), 7.05-7.09 (m, 1H), 7.11-7.17 (m, 2H), 7.22 (dd,J=7.6, 1.2 Hz, 1H).

The product was converted to a hydrochloride by a method similar toExample (4g) to give 92 mg of the title compound as colorless crystals.

MS m/e (ESI) 343 (MH⁺).

Example 321-Butyl-4-[4-(4-methoxypiperidin-1-yl)-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

32a4-Methoxy-1-[4-nitro-3-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperidine

Trifluoromethanesulfonic acid 5-(4-methoxypiperidin-1-yl)-2-nitrophenylester (3 g, 7.81 mmol) prepared in Example (7c) was used as the startingmaterial.4,4,5,5-Tetramethyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)-[1,3,2]dioxaborolaneprepared in Example (4b) was used instead of4-t-butylcyclohex-1-enyl-(4,4,5,5-tetramethyl)-[1,3,2]dioxaborolane, anda mixed solvent of 1,2-dimethoxyethane-water was used as the solvent,for reaction in a manner similar to Example (7e) and treated in asimilar manner, to give 2.89 g of the title compound as a yellow oil.

32b4-(4-Methoxypiperidin-1-yl)-2-(3,3,5,5-tetramethylcyclohexyl)phenylamine

4-Methoxy-1-[4-nitro-3-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperidine(1 g, 2.68 mmol) prepared in Example (32a) was used as the startingmaterial.

Reaction and treatment were carried out in a manner similar to Example(2c), using a mixed solvent of methanol-tetrahydrofuran instead of ethylacetate and changing the reaction time to 18 hours and 40 minutes, togive 845 mg of the title compound as a light brown oil.

32c1-[4-(4-Methoxypiperidin-1-yl)-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine

4-(4-Methoxypiperidin-1-yl)-2-(3,3,5,5-tetramethylcyclohexyl)phenylamine(843 mg, 2.45 mmol) prepared in Example (32b) was used as the startingmaterial.

This was reacted and treated in a manner similar to Example (7g), togive 596 mg of the title compound as a light brown solid.

32d1-Butyl-4-[4-(4-methoxypiperidin-1-yl)-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

1-[4-(4-Methoxypiperidin-1-yl)-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine(120 mg, 0.29 mmol) prepared in Example (32c) was used as the startingmaterial.

This was reacted and treated in a manner similar to Example (4g), togive 130 mg of1-butyl-4-[4-(4-methoxypiperidin-1-yl)-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazineas a light yellow solid.

The product was converted to a hydrochloride by a method similar toExample (4g) to give 143 mg of the title compound as a light brownsolid.

MS m/e (ESI) 470 (MH⁺).

Example 33 1-Butyl-4-(2-spiro[4.5]dec-8-ylphenyl)piperazinehydrochloride

33a Spiro[4.5]dec-6-en-8-one

To a solution of cyclopentanecarbaldehyde (10 g, 100 mmol) in toluene(100 mL) were added methyl vinyl ketone (7.8 g, 110 mmol) andp-toluenesulfonic acid (1.9 g, 10 mmol), and the mixture was stirred at120° C. for 3 hours, using a Dean-Stark apparatus to remove water. Thereaction mixture was air-cooled to room temperature, then saturatedaqueous sodium hydrogencarbonate was added, and the mixture wasextracted with ethyl acetate. The organic layer was dried over anhydrousmagnesium sulfate. The desiccant was filtered off and the filtrate wasconcentrated under reduced pressure. The resultant residue was purifiedby silica gel column chromatography (ethyl acetate/hexane) to give 6.0 gof the title compound as a red oil.

33b Spiro[4.5]decan-8-one

Spiro[4.5]dec-6-en-8-one (6.0 g, 40 mmol) prepared in Example (33a) wasused for reaction in a manner similar to Example (6a) and treated in asimilar manner, to give 6.0 g of the title compound as a red oil.

33c Trifluoromethanesulfonic acid spiro[4.5]dec-7-en-8-yl ester

Spiro[4.5]decan-8-one (7.0 g, 46 mmol) prepared in Example (33b) wasused for reaction in a manner similar to Example (6b) and treated in asimilar manner, to give 3.7 g of the title compound as a yellow oil.

33d 4,4,5,5-Tetramethyl-2-spiro[4.5]dec-7-en-8-yl-[1,3,2]dioxaborolane

Trifluoromethanesulfonic acid spiro[4.5]dec-7-en-8-yl ester (3.7 g, 40mmol) prepared in Example (33c) was used for reaction in a similarmanner and treatment in a manner similar to Example (6c), to give 3.3 gof the title compound as a light yellow oil.

33e 4-(2-Spiro[4.5]dec-7-en-8-ylphenyl)piperazine-1-carboxylic acidt-butyl ester

The 4,4,5,5-tetramethyl-2-spiro[4.5]dec-7-en-8-yl-[1,3,2]dioxaborolane(1.3 g, 4.95 mmol) prepared in Example (33d) was used for reaction in amanner similar to Example (4e) and treated in a similar manner, to give1.0 g of the title compound as a light yellow oil.

33f 1-(2-Spiro[4.5]dec-7-en-8-ylphenyl)piperazine

4-(2-Spiro[4.5]dec-7-en-8-ylphenyl)piperazine-1-carboxylic acid t-butylester (1.0 g, 2.5 mmol) prepared in Example (33e) was used for reactionin a manner similar to Example (4f) and treated in a similar manner, togive 0.6 g of the title compound as a yellow oil.

33g 1-Butyl-4-(2-spiro[4.5]dec-7-en-8-ylphenyl)piperazine hydrochloride

1-(2-Spiro[4.5]dec-7-en-8-ylphenyl)piperazine (140 mg, 0.47 mmol)prepared in Example (33f) was used for reaction in a manner similar toExample (4g) and treated in a similar manner, to give 125 mg of thetitle compound as a light yellow solid.

MS m/e (ESI) 353 (MH⁺).

33h 1-Butyl-4-(2-spiro[4.5]dec-8-ylphenyl)piperazine hydrochloride

1-Butyl-4-(2-spiro[4.5]dec-7-en-8-ylphenyl)piperazine hydrochloride (40mg, 0.10 mmol) prepared in Example (33g) was used for reaction in amanner similar to Example (6h) and treated in a similar manner, to give33 mg of the title compound as a light yellow solid.

MS m/e (ESI) 355 (MH⁺).

Example 34 1-Isobutyl-4-(2-spiro[2.5]oct-5-en-6-ylphenyl)piperazinehydrochloride

34a Trifluoromethanesulfonic acid sipiro[2.5]oct-5-en-6-yl ester

Spiro[2.5]octan-2-one (1.71 g, 13.77 mmol) was used as the startingmaterial instead of 4,4-diethylcyclohexanone for reaction in a mannersimilar to Example (6b) and treated in a similar manner, to give 3.35 gof the title compound as a brown oil.

34b 4,4,5,5-Tetramethyl-2-spiro[2.5]oct-5-en-6-yl-[1,3,2]dioxaborolane

Trifluoromethanesulfonic acid spiro[2.5]oct-5-en-6-yl ester (3.34 g,13.03 mmol) prepared in Example (34a) was used as the starting materialinstead of trifluoromethanesulfonic acid 4,4-diethylcyclohex-1-enylester for reaction in a manner similar to Example (6c) and treated in asimilar manner, to give 2.35 g of the title compound as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.25-0.30 (m, 4H), 1.27 (s, 12H), 1.34-1.37(m, 2H), 1.97-1.99 (m, 2H), 2.19-2.23 (m, 2H), 6.55-6.60 (m, 1H).

34c 4-(2-Spiro[2.5]oct-5-en-6-ylphenyl)piperazine-1-carboxylic acidt-butyl ester

4-(2-Trifluoromethanesulfonyloxyphenyl)piperazine-1-carboxylic acidt-butyl ester (4.12 g, 10.03 mmol) prepared in Example (4d) was used asthe starting material.

4,4,5,5-Tetramethyl-2-spiro[2.5]oct-5-en-6-yl-[1,3,2]dioxaborolane (2.35g, 10.03 mmol) prepared in Example (34b) was used instead of4,4,5,5-tetramethyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)[1,3,2]dioxaborolanefor reaction in a manner similar to Example (4e) and treated in asimilar manner, to give 3.09 g of the title compound as a light yellowsolid.

34d 1-(2-Spiro[2.5]oct-5-en-6-ylphenyl)piperazine

4-(2-Spiro[2.5]oct-5-en-6-ylphenyl)piperazine-1-carboxylic acid t-butylester (0.380 g, 1.03 mmol) prepared in Example (34c) was used as thestarting material for reaction in a manner similar to Example (4f) andtreated in a similar manner, to give 249 mg of the title compound as alight brown oil.

34e 1-Isobutyl-4-(2-spiro[2.5]oct-5-en-6-ylphenyl)piperazinehydrochloride

1-(2-Spiro[2.5]oct-5-en-6-ylphenyl)piperazine (66 mg, 0.246 mmol)prepared in Example (34d) was used as the starting material.

Isobutyraldehyde was used instead of tetrahydropyran-4-carbaldehyde forreaction in a manner similar to Example (6g) and treated in a similarmanner, to give 76 mg of the title compound as colorless crystals.

MS m/e (ESI) 325 (MH⁺).

Example 351-(2-Spiro[2.5]oct-5-en-6-ylphenyl)-4-(tetrahydropyran-4-ylmethyl)piperazinehydrochloride

1-(2-Spiro[2.5]oct-5-en-6-ylphenyl)piperazine (20 mg, 0.0745 mmol)prepared in Example (34d) was used as the starting material.

Reaction and treatment were carried out in a manner similar to Example(6g), to give 24.3 mg of the title compound as a colorless solid.

MS m/e (ESI) 367 (MH⁺).

Example 36 1-Isobutyl-4-(2-spiro[2.5]oct-6-ylphenyl)piperazinehydrochloride

1-Isobutyl-4-(2-spiro[2.5]oct-5-en-6-ylphenyl)piperazine hydrochloride(20 mg, 0.0554 mmol) prepared in Example (34e) was used as the startingmaterial.

Reaction were carried out in a manner similar to Example (6h) andstirring was continued for 6 hours, treatment was carried out in asimilar manner to give 19 mg of the title compound as colorlesscrystals.

MS m/e (ESI) 327 (MH⁺).

Example 371-[2-(4,4-Dimethylcyclohex-1-enyl)phenyl]-4-isobutylpiperazinehydrochloride

37a 4-[2-(4,4-Dimethylcyclohex-1-enyl)phenyl]piperazine-1-carboxylicacid t-butyl ester

4-(2-Trifluoromethanesulfonyloxyphenyl)piperazine-1-carboxylic acidt-butyl ester (4.1 g, 10 mmol) prepared in Example (4d) was used as thestarting material.

2-(4,4-Dimethylcyclohex-1-enyl)-4,4,5,5-tetramethyl[1,3,2]dioxaborolane(2.83 g, 12 mmol) prepared in Example (1b) was used instead of4,4,5,5-tetramethyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)[1,3,2]dioxaborolanefor reaction in a manner similar to Example (4e) and treated in asimilar manner, to give 3.29 g of the title compound as a colorlesssolid.

37b 1-[2-(4,4-Dimethylcyclohex-1-enyl)phenyl]piperazine

4-[2-(4,4-Dimethylcyclohex-1-enyl)phenyl]piperazine-1-carboxylic acidt-butyl ester (3.17 g, 8.56 mmol) prepared in Example (37a) was used asthe starting material.

Dichloromethane was used instead of a mixed solvent of ethylacetate-dichloromethane for reaction in a manner similar to Example (3g)and treated in a similar manner, to give 1.82 g of the title compound asa light green solid.

37c 1-[2-(4,4-Dimethylcyclohex-1-enyl)phenyl]-4-isobutylpiperazineehydrochloride

1-[2-(4,4-Dimethylcyclohex-1-enyl)phenyl]piperazine (200 mg, 0.740 mmol)prepared in Example (37b) was used as the starting material.

Reaction and treatment were carried out in a manner similar to Example(3h), to give 230 mg of1-[2-(4,4-dimethylcyclohex-1-enyl)phenyl]-4-isobutylpiperazinee as alight yellow oil.

This was converted to a hydrochloride by a method similar to Example(3h) to give 255 mg of the title compound as a colorless solid.

MS m/e (ESI) 327 (MH⁺).

Example 381-Cyclopropylmethyl-4-[2-(4,4-dimethylcyclohexyl)-4-(4-methoxypiperidin-1-yl)phenyl]piperazinehydrochloride

38a 4-[2-(4,4-Diethylcyclohex-1-enyl)phenyl]piperazine-1-carboxylic acidt-butyl ester

4-(2-Trifluoromethanesulfonyloxyphenyl)piperazine-1-carboxylic acidt-butyl ester (4.71 g, 11.5 mmol) prepared in Example (4d) was used asthe starting material.

2-(4,4-Diethylcyclohex-1-enyl)-4,4,5,5-tetramethyl[1,3,2]dioxaborolane(3.7 g, 14.0 mmol) prepared in Example (6c) was used instead of4,4,5,5-tetramethyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)[1,3,2]dioxaborolanefor reaction in a manner similar to Example (4e) and treated in asimilar manner, to give 3.94 g of the title compound as a brown oil.

38b 4-[2-(4,4-Diethylcyclohexyl)phenyl]piperazine-1-carboxylic acidt-butyl ester

4-[2-(4,4-Diethylcyclohex-1-enyl)phenyl]piperazine-1-carboxylic acidt-butyl ester (3.96 g, 9.93 mmol) prepared in Example (38a) was used asthe starting material.

Methanol alone was used as the solvent instead of a mixed solvent oftetrahydrofuran-methanol, for reaction in a manner similar to Example(8a) and treated in a similar manner. The resultant crude product waspurified by silica gel column chromatography (ethyl acetate/hexane) togive 3.79 g of the title compound as a yellow oil.

38c 4-[4-Bromo-2-(4,4-dimethylcyclohexyl)phenyl]piperazine-1-carboxylicacid t-butyl ester

4-[2-(4,4-Diethylcyclohexyl)phenyl]piperazine-1-carboxylic acid t-butylester (3.79 g, 9.46 mmol) prepared in Example (38b) was used as thestarting material.

This was reacted and treated in a manner similar to Example (3e), togive 2.75 g of the title compound as a white solid.

38d4-[2-(4,4-Diethylcyclohexyl)-4-(4-methoxypiperidin-1-yl)phenyl]piperazine-1-carboxylicacid t-butyl ester

4-[4-Bromo-2-(4,4-dimethylcyclohexyl)phenyl]piperazine-1-carboxylic acidt-butyl ester (900 mg, 1.88 mmol) prepared in Example (38c) wasdissolved in xylene (10 mL). 4-Methoxypiperidine hydrochloride (430 mg,2.84 mmol) prepared in Example (7a), sodium t-butoxide (810 mg, 8.43mmol), tri-t-butylphosphonium tetrafluoroborate (340 mg, 1.17 mmol) andpalladium(II) acetate (105 mg, 0.47 mmol) were added to the mixedsolution, and the mixture was stirred at an external temperature of 100°C. for 1 hour under nitrogen atmosphere.

Treatment was then carried out in a manner similar to Example (3f) togive 413 mg of the title compound as a light red solid.

38e1-[2-(4,4-Diethylcyclohexyl)-4-(4-methoxypiperidin-1-yl)phenyl]piperazine

4-[2-(4,4-Diethylcyclohexyl)-4-(4-methoxypiperidin-1-yl)phenyl]piperazine-1-carboxylicacid t-butyl ester (413 mg, 0.80 mmol) prepared in Example (38d) wasused as the starting material.

This was reacted in a manner similar to Example (8b), and treated in asimilar manner using potassium carbonate instead of 5N aqueous sodiumhydroxide, to give 283 mg of the title compound as a white solid.

38f1-Cyclopropylmethyl-4-[2-(4,4-dimethylcyclohexyl)-4-(4-methoxypiperidinyl)phenyl]piperazine hydrochloride

1-[2-(4,4-Diethylcyclohexyl)-4-(4-methoxypiperidin-1-yl)phenyl]piperazine(50 mg, 0.121 mmol) prepared in Example (38e) was used as the startingmaterial.

This was reacted and treated in a manner similar to Example (9). Theproduct was then converted to a hydrochloride by a method similar toExample (9) to give 60 mg of the title compound as a white solid.

MS m/e (ESI) 468 (MH⁺).

Example 391-Butyl-4-[4-(4-methoxypiperidin-1-yl)-2-spiro[5.5]undec-3-yl-phenyl]piperazine

39a Trifluoromethanesulfonic acid spiro[5.5]undec-2-en-3-yl ester

Spiro[5.5]undecan-3-one (15 g, 90.2 mmol) was used as the startingmaterial instead of 4,4-diethylcyclohexanone for reaction in a mannersimilar to Example (6b) and treated in a similar manner, to give 20.9 gof the title compound as a brown oil.

39b 4,4,5,5-Tetramethyl-2-spiro[5.5]undec-2-en-3-yl-[1,3,2]dioxaborolane

Trifluoromethanesulfonic acid spiro[5.5]undec-2-en-3-yl ester (10 g,33.5 mmol) prepared in Example (39a) was used as the starting materialinstead of trifluoromethanesulfonic acid 4,4-diethylcyclohex-1-enylester for reaction in a manner similar to Example (6c) and treated in asimilar manner, to give 7.64 g of the title compound as a yellow solid.

39c 4-Methoxy-1-(4-nitro-3-spiro[5.5]undec-2-en-3-yl-phenyl)piperidine

Trifluoromethanesulfonic acid 5-(4-methoxypiperidin-1-yl)-2-nitrophenylester (2.0 g, 5.43 mmol) prepared in Example (7c) was used as thestarting material.4,4,5,5-Tetramethyl-2-spiro[5.5]undec-2-en-3-yl-[1,3,2]dioxaborolane(1.65 g, 5.97 mmol) prepared in Example (39b) was used instead of4-t-butylcyclohex-1-enyl-(4,4,5,5-tetramethyl)-[1,3,2]dioxaborolane forreaction in a manner similar to Example (7e) and treated in a similarmanner, to give 2.331 g of the title compound as an orange oil.

39d 4-(4-Methoxypiperidin-1-yl)-2-spiro[5.5]undec-2-en-3-yl)phenylamine

4-Methoxy-1-(4-nitro-3-spiro[5.5]undec-2-en-3-yl-phenyl)piperidine(2.331 g, 6.06 mmol) prepared in Example (39c) was used as the startingmaterial for reaction in a manner similar to Example (6e) and treated ina similar manner, to give 1.79 g of the title compound as a yellow oil.

39e1-[4-(4-Methoxypiperidin-1-yl)-2-spiro[5.5]undec-2-en-3-yl-phenyl]piperazine

4-(4-Methoxypiperidin-1-yl)-2-spiro[5.5]undec-2-en-3-yl)phenylamine(1.79 g, 5.03 mmol) prepared in Example (39d) was used as the startingmaterial for reaction in a manner similar to Example (7g) and treated ina similar manner, to give 1.071 g of the title compound as a lightyellow solid.

39f4-[4-(4-Methoxypiperidin-1-yl)-2-spiro[5.5]undec-2-en-3-ylphenyl]piperazine-1-carboxylicacid t-butyl ester

1-[4-(4-Methoxypiperidin-1-yl)-2-spiro[5.5]undec-2-en-3-yl-phenyl]piperazine(450 mg, 1.062 mmol) prepared in Example (39e) was used as the startingmaterial for reaction in a manner similar to Example (3d) and treated ina similar manner, to give 524 mg of the title compound as a colorlesssolid.

39g4-[4-(4-Methoxypiperidin-1-yl)-2-spiro[5.5]undec-3-ylphenyl]piperazine-1-carboxylicacid t-butyl ester

4-[4-(4-Methoxypiperidin-1-yl)-2-spiro[5.5]undec-2-en-3-ylphenyl]piperazine-1-carboxylicacid t-butyl ester (524 mg, 1.0 mmol) prepared in Example (39f) was usedas the starting material. A mixed solution of methanol, tetrahydrofuranand ethyl acetate was used instead of a mixed solvent of methanol andtetrahydrofuran for reaction in a manner similar to Example (8a) andtreated in a similar manner, to give 517 mg of the title compound as acolorless solid.

39h1-[4-(4-Methoxypiperidin-1-yl)-2-spiro[5.5]undec-3-ylphenyl]piperazine

4-[4-(4-Methoxypiperidin-1-yl)-2-spiro[5.5]undec-3-ylphenyl]piperazine-1-carboxylicacid t-butyl ester (517 mg, 0.983 mmol) prepared in Example (39g) wasused as the starting material for reaction in a manner similar toExample (8b) and treated in a similar manner, to give 367 mg of thetitle compound as a light yellow solid.

39i1-Butyl-4-[4-(4-methoxypiperidin-1-yl)-2-spiro[5.5]undec-3-ylphenyl]piperazinehydrochloride

1-[4-(4-Methoxypiperidin-1-yl)-2-spiro[5.5]undec-3-ylphenyl]piperazine(50 mg, 0.117 mmol) prepared in Example (39h) was used as the startingmaterial for reaction in a manner similar to Example (7h) and treated ina similar manner, to give 23 mg of1-butyl-4-[4-(4-methoxypiperidin-1-yl)-2-spiro[5.5]undec-3-ylphenyl]piperazineas a colorless solid.

This was converted to a hydrochloride by a method similar to Example(7h) to give 28 mg of the title compound as a colorless solid.

MS m/e (ESI) 482 (MH⁺).

Example 40{4-[2-(3,3,5,5-Tetramethylcyclohexyl)phenyl]piperazin-1-yl}acetonitrilehydrochloride

1-[2-(3,3,5,5-Tetramethylcyclohexyl)phenyl]piperazine (40 mg, 0.133mmol) prepared in Example (8b) was used as the starting material.

Bromoacetonitrile was used instead of 2-chloro-N-ethylacetamide forreaction in a manner similar to Example (10b) and treated in a similarmanner.

The obtained product was then converted to a hydrochloride by a methodsimilar to Example (10b) to give 28 mg of the title compound as acolorless solid.

MS m/e (ESI) 340 (MH⁺).

Example 411-(2-Ethoxyethyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

1-[2-(3,3,5,5-Tetramethylcyclohexyl)phenyl]piperazine (40 mg, 0.133mmol) prepared in Example (8b) was used as the starting material.

2-Bromoethyl ethyl ether was used instead of 2-chloro-N-ethylacetamidefor reaction in a manner similar to Example (10b) and treated in asimilar manner.

The obtained product was then converted to a hydrochloride by a methodsimilar to Example (10b) to give 34 mg of the title compound as acolorless solid.

MS m/e (ESI) 373 (MH⁺).

Example 421-Cyclopropylmethyl-4-[2-(4,4-dimethylcyclohexyl)-4-piperidin-1-ylphenyl]piperazinehydrochloride

42a4-[2-(4,4-Dimethylcyclohexyl)-4-piperidin-1-ylphenyl]piperazine-1-carboxylicacid t-butyl ester

4-[4-Bromo-2-(4,4-dimethylcyclohexyl)phenyl]piperazine-1-carboxylic acidt-butyl ester (800 mg, 1.77 mmol) prepared in Example (3e) was used asthe starting material.

Piperidine was used instead of morpholine for reaction in a mannersimilar to Example (3f) and treated in a similar manner, to give 597 mgof the title compound as a colorless solid.

42b 1-[2-(4,4-Dimethylcyclohexyl)-4-piperidin-1-ylphenyl]piperazine

4-[2-(4,4-dimethylcyclohexyl)-4-piperidin-1-ylphenyl]piperazine-1-carboxylicacid t-butyl ester (597 mg, 1.31 mmol) prepared in Example (42a) wasused as the starting material.

Reaction and treatment were carried out in a manner similar to Example(3g), to give 419 mg of the title compound as a colorless solid.

42c1-Cyclopropylmethyl-4-[2-(4,4-dimethylcyclohexyl)-4-piperidin-1-ylphenyl]piperazinehydrochloride

1-[2-(4,4-Dimethylcyclohexyl)-4-piperidin-1-ylphenyl]piperazine (50 mg,0.141 mmol) prepared in Example (42b) was used as the starting material.

Cyclopropanecarbaldehyde was used instead of isobutyraldehyde forreaction in a manner similar to Example (3h) and treated in a similarmanner.

The obtained product was then converted to a hydrochloride by a methodsimilar to Example (3h) to give 65 mg of the title compound as acolorless solid.

MS m/e (ESI) 410 (MH⁺).

Example 434-[4-(4-Butylpiperazin-1-yl)-5-(4,4-dimethylcyclohexyl)-2-methoxyphenyl]-morpholinehydrochloride

43a4-[2-(4,4-Diethylcyclohex-1-enyl)-5-methoxyphenyl]piperazine-1-carboxylicacid t-butyl ester

1-[2-(4,4-Diethylcyclohex-1-enyl)-5-methoxyphenyl]piperazine (0.9 g, 2.7mmol) prepared in Example (6f) was used for reaction in a manner similarto Example (3d) and treated in a similar manner, using tetrahydrofuraninstead of dichloromethane as the solvent according to Example (3d), togive 0.96 g of the title compound as a light yellow oil.

43b 1-[2-(4,4-Diethylcyclohexyl)-5-methoxyphenyl]piperazine-1-carboxylicacid t-butyl ester

4-[2-(4,4-diethylcyclohex-1-enyl)-5-methoxyphenyl]piperazine-1-carboxylicacid t-butyl ester (0.96 g, 2.2 mmol) prepared in Example (43a) was usedfor reaction in a manner similar to Example (8a) and treated in asimilar manner, using methanol instead of a mixed solvent of methanoland tetrahydrofuran, to give 0.95 g of the title compound as a lightyellow oil.

43c4-[4-Bromo-2-(4,4-dimethylcyclohexyl)-5-methoxyphenyl]piperazine-1-carboxylicacid t-butyl ester

Reaction was carried out in a manner similar to Example (3e), using asthe starting material the1-[2-(4,4-dimethylcyclohexyl)-5-methoxyphenyl]piperazine-1-carboxylicacid t-butyl ester (0.9 g, 2.08 mmol) prepared in Example (43b)according to Example (3e), and using acetonitrile instead of methanoland N-bromosuccinimide instead of bromine. Saturated aqueous sodiumhydrogencarbonate was added to the reaction mixture and the mixture wasextracted with ethyl acetate, after which treatment was carried out in asimilar manner to give 0.41 g of the title compound as a light yellowoil.

43d4-[2-(4,4-Diethylcyclohexyl)-4-morpholino-5-methoxyphenyl]piperazine-1-carboxylicacid t-butyl ester

Reaction and treatment were carried out in a manner similar to Example(3f), using4-[4-bromo-2-(4,4-dimethylcyclohexyl)-5-methoxyphenyl]piperazine-1-carboxylicacid t-butyl ester (200 mg, 0.39 mmol) prepared in Example (43c) as thestarting material and using tri-t-butylphosphine instead oftri-t-butylphosphonium tetrafluoroborate, to give 80 mg of the titlecompound as a yellow oil.

43e4-[5-(4,4-Diethylcyclohexyl)-2-methoxy-4-piperazin-1-ylphenyl]morpholine

Reaction and treatment were carried out in a manner similar to Example(8b), using4-[2-(4,4-dimethylcyclohexyl)-4-morpholino-5-methoxyphenyl]piperazine-1-carboxylicacid t-butyl ester (80 mg, 0.2 mmol) prepared in Example (43d) to give40 mg of the title compound as a yellow solid.

43f4-[4-(4-Butylpiperazin-1-yl)-5-(4,4-dimethylcyclohexyl)-2-methoxyphenyl]-morpholinehydrochloride

4-[5-(4,4-Diethylcyclohexyl)-2-methoxy-4-piperazin-1-ylphenyl]morpholine(20 mg, 0.048 mmol) prepared in Example (43e) was reacted and treated ina manner similar to Example (6g), using butyraldehyde instead oftetrahydropyran-4-carbaldehyde, to give 11 mg of the title compound as alight yellow solid.

MS m/e (ESI) 472 (MH⁺).

Example 44 1-Butyl-4-(2-cycloheptylphenyl)piperazine hydrochloride

44a 1-(2-Nitrophenyl)cycloheptene

A mixture of trifluoromethanesulfonic acid cyclopent-1-enyl ester (2.50g, 10.2 mmol), 2-nitrophenylboronic acid (2.04 g, 12.2 mmol),tetrakis(triphenylphosphine)palladium(0) (612 mg, 0.53 mmol), 2N aqueoussolution of sodium carbonate (10.2 mL), toluene (32 mL) and ethanol (16mL) was stirred for 2 hours and 30 minutes at an external temperature of90° C. under a nitrogen atmosphere.

Ethyl acetate and brine were added to the reaction mixture andextraction was performed twice with ethyl acetate. The separated organiclayer was dried over anhydrous sodium sulfate. The desiccant wasfiltered off and the filtrate was concentrated under reduced pressure.The obtained residue was purified by silica gel column chromatography(ethyl acetate/heptane) to give 1.937 g of the title compound as a lightyellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.55-1.67 (m, 4H), 1.78-1.84 (m, 2H),2.25-2.29 (m, 2H), 2.42-2.44 (m, 2H), 5.83 (t, J=6.4 Hz, 1H), 7.28 (dd,J=7.6, 1.2 Hz, 1H), 7.34 (ddd, J=8.0, 7.6, 1.2 Hz, 1H), 7.49 (ddd,J=7.6, 7.6, 1.2 Hz, 1H), 7.81 (dd, J=8.0, 1.2 Hz, 1H).

44b 2-Cycloheptylphenylamine

A mixture of the 1-(2-nitrophenyl)cycloheptene (1.00 g, 4.61 mmol)produced in Example (44a), 10% palladium on carbon (300 mg, wet) andmethanol (130 mL) was stirred for 21 hours at atmospheric pressure androom temperature under a hydrogen atmosphere. The reaction mixture wasfiltered and the filtrate was concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography (ethylacetate/heptane) to give 539 mg of the title compound as a light orangeoil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.49-1.78 (m, 8H), 1.80-1.87 (m, 2H),1.91-1.96 (m, 2H), 2.60-2.70 (m, 1H), 3.61 (brs, 2H), 6.67 (dd, J=7.6,1.2 Hz, 1H), 6.76 (dd, J=7.6, 7.6 Hz, 1H), 6.99 (ddd, J=7.6, 7.6, 1.2Hz, 1H), 7.11 (d, J=7.6 Hz, 1H).

44c 1-(2-Cycloheptylphenyl)piperazine

To a solution of the 2-cycloheptylphenylamine (539 mg, 2.85 mmol)produced in Example (44b) in 1,2-dichlorobenzene (7 mL) was addedbis(2-chloroethyl)amine hydrochloride (610 mg, 3.42 mmol), and themixture was stirred at an external temperature of 200° C. under anitrogen atmosphere. During the reaction, a nitrogen stream was blowninto the reactor to remove the hydrogen chloride gas in the reactor.This procedure was repeated several times. After 8 hours, the mixturewas air-cooled to room temperature. To the reaction mixture were addedaqueous solution of potassium carbonate, ethyl acetate and methanol, andextraction was performed three times with ethyl acetate. The obtainedorganic layers were dried over anhydrous sodium sulfate, and then thedesiccant was filtered off and the filtrate was concentrated underreduced pressure. The obtained residue was purified by NH silica gelcolumn chromatography (ethyl acetate/heptane) to give 540 mg of thetitle compound as a brown oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.50-1.84 (m, 12H), 2.82-2.84 (m, 4H),3.01-3.03 (m, 4H), 3.28 (tt, J=10.0, 2.8 Hz, 1H), 7.03-7.07 (m, 2H),7.12 (ddd, J=8.4, 6.8, 1.6 Hz, 1H), 7.20 (dd, J=7.6, 1.6 Hz, 1H).

The 1H of NH could not be identified.

44d 1-Butyl-4-(2-cycloheptylphenyl)piperazine hydrochloride

To a mixture of the 1-(2-cycloheptylphenyl)piperazine (25 mg, 0.0967mmol) produced in Example (44c) and tetrahydrofuran (1 mL) were addedbutyraldehyde (0.011 mL, 0.126 mmol), sodium triacetoxyborohydride (26.6mg, 0.126 mmol) and acetic acid (0.011 mL, 0.183 mmol), and the mixturewas stirred for 19 hours and 30 minutes at room temperature. Saturatedaqueous solution of sodium hydrogencarbonate was added to the reactionmixture and extraction was performed three times with ethyl acetate. Theobtained organic layers were concentrated. The resultant residue waspurified by NH silica gel column chromatography (ethyl acetate/heptane)to give 26.7 mg of 1-butyl-4-(2-cycloheptylphenyl)piperazine as acolorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.95 (t, J=7.2 Hz, 3H), 1.32-1.41 (m, 2H),1.49-1.84 (m, 14H), 2.39-2.43 (m, 2H), 2.61 (brs, 4H), 2.89-2.92 (m,4H), 3.27 (tt, J=10.0, 3.2 Hz, 1H), 7.03-7.15 (m, 3H), 7.21 (dd, J=7.6,1.6 Hz, 1H).

This compound was dissolved in dichloromethane (1 mL) and a 4N solutionof hydrogen chloride in ethyl acetate (0.0425 mL, 0.17 mmol) was added.This solution was concentrated under reduced pressure, and diethyl etherwas added to the resultant residue to produce a solid, which was thentriturated by sonication. This solid was filtered and then dried underreduced pressure to give 28.5 mg of the title compound as a colorlesssolid.

MS m/e (ESI) 315 (MH⁺).

Example 45 1-Butyl-4-(2-cyclohept-1-enylphenyl)piperazine hydrochloride

45a 1-(2-Cyclohept-1-enylphenyl)piperazine

To a solution of 2-cyclohept-1-enylphenylamine (617 mg, 3.29 mmol) in1,2-dichlorobenzene (8 mL) was added bis(2-chloroethyl)aminehydrochloride (705 mg, 3.95 mmol), and the mixture was stirred at anexternal temperature of 200° C. under a nitrogen atmosphere. During thereaction, a nitrogen stream was blown into the reactor to remove thehydrogen chloride gas in the reactor. This procedure was repeatedseveral times. After 5 hours, the reaction mixture was air-cooled toroom temperature, and then aqueous solution of potassium carbonate,ethyl acetate and methanol were added to the reaction mixture andextraction was performed three times with ethyl acetate. The obtainedorganic layers were dried over anhydrous sodium sulfate, and then thedesiccant was filtered off and the filtrate was concentrated underreduced pressure. The resultant residue was purified by NH silica gelcolumn chromatography (ethyl acetate/heptane) to give 387 mg of thetitle compound as a brown oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.54-1.63 (m, 4H), 1.78-1.84 (m, 2H),2.23-2.27 (m, 2H), 2.55-2.58 (m, 2H), 2.92-3.01 (m, 8H), 5.85 (t, J=6.4Hz, 1H), 6.94-6.98 (m, 2H), 7.09 (ddd, J=7.6, 1.6, 1.6 Hz, 1H), 7.20(ddd, J=8.0, 7.6, 1.6 Hz, 1H).

The 1H of NH could not be identified.

45b 1-Butyl-4-(2-cyclohept-1-enylphenyl)piperazine hydrochloride

To a solution of the 1-(2-cyclohept-1-enylphenyl)piperazine (20 mg,0.0780 mmol) produced in Example (45a) in tetrahydrofuran (1 mL) wereadded butyraldehyde (0.009 mL, 0.1014 mmol), sodiumtriacetoxyborohydride (21.5 mg, 0.1014 mmol) and acetic acid (0.009 mL,0.1482 mmol), and the mixture was stirred for 23 hours and 10 minutes atroom temperature.

Saturated aqueous solution of sodium hydrogencarbonate was added to thereaction mixture and extraction was performed three times with ethylacetate. The organic layers was concentrated to produce a residue, whichwas purified by NH silica gel column chromatography (ethylacetate/heptane) to give 19 mg of1-butyl-4-(2-cyclohept-1-enylphenyl)piperazine as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.94 (t, J=7.2 Hz, 3H), 1.35 (tq, J=7.2, 7.2Hz, 2H), 1.48-1.61 (m, 8H), 1.78-1.84 (m, 2H), 2.23-2.27 (m, 2H),2.37-2.40 (m, 2H), 2.54-2.57 (m, 4H), 3.03 (brs, 4H), 5.85 (t, J=6.4 Hz,1H), 6.93-6.99 (m, 2H), 7.08 (dd, J=7.6, 1.6 Hz, 1H), 7.19 (ddd, J=8.8,7.2, 1.6 Hz, 1H).

This compound was dissolved in dichloromethane (1 mL) and a 4N solutionof hydrogen chloride in ethyl acetate (0.0304 mL, 0.1216 mmol) wasadded.

The resulting solution was concentrated by nitrogen stream, and thendiethyl ether was added to the resultant residue to produce a solid. Thesolid was triturated by sonication and the supernatant diethyl ethersolution was removed. It was then dried under reduced pressure to give20.3 mg of the title compound as a colorless solid.

MS m/e (ESI) 313 (MH⁺).

Example 46 1-(2-Cyclooctylphenyl)-4-isobutylpiperazinee hydrochloride

46a 1-(2-Cyclooct-1-enylphenyl)piperazine

To a solution of 2-cyclooct-1-enylphenylamine (140 mg, 0.695 mmol) in1,2-dichlorobenzene (2 mL) was added bis(2-chloroethyl)aminehydrochloride (149 mg, 0.835 mmol), and the mixture was stirred at anexternal temperature of 200° C. under a nitrogen atmosphere. During thereaction, a nitrogen stream was blown into the reactor to remove thehydrogen chloride gas in the reactor. This procedure was repeatedseveral times. After 9 hours, the mixture was air-cooled to roomtemperature. Aqueous solution of potassium carbonate, ethyl acetate andmethanol were added to the reaction mixture and extraction was performedthree times with ethyl acetate. The obtained organic layers were driedover anhydrous sodium sulfate. The desiccant was filtered off and thefiltrate was concentrated under reduced pressure. The resultant residuewas purified by NH silica gel column chromatography (ethylacetate/heptane) to give 100 mg of the title compound as a brown oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.35-1.77 (m, 8H), 2.23-2.28 (m, 2H),2.74-2.77 (m, 2H), 2.94-3.02 (m, 8H), 5.63 (t, J=8.0 Hz, 1H), 6.93-6.97(m, 2H), 7.08 (dd, J=7.6, 2.0 Hz, 1H), 7.21 (ddd, J=7.6, 7.6, 2.0 Hz,1H).

The 1H of NH could not be identified.

46b 4-(2-Cyclooct-1-enylphenyl)piperazine-1-carboxylic acid t-butylester

To 1-(2-cyclooct-1-enylphenyl)piperazine (100 mg, 0.37 mmol) produced inExample (46a) dissolved in dichloromethane (2.3 mL) were addeddi-t-butyl dicarbonate (96.9 mg, 0.444 mmol) and triethylamine (0.0645mL, 0.463 mmol), and the mixture was stirred for 13 hours at roomtemperature. Then, di-t-butyl dicarbonate (15 mg, 0.0687 mmol) and4-dimethylaminopyridine (10 mg, 0.0819 mmol) were further added theretoand followed by stirring for 30 minutes at room temperature.

Brine was added to the reaction mixture and extraction was performedtwice with dichloromethane. The separated organic layer was dried overanhydrous sodium sulfate. The desiccant was filtered off and thefiltrate was concentrated under reduced pressure. The resultant residuewas purified by NH silica gel column chromatography (ethylacetate/heptane) to give 128 mg of the title compound as a light yellowoil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.35-1.70 (m, 17H), 2.23-2.28 (m, 2H),2.71-2.74 (m, 2H), 2.95-2.98 (m, 4H), 3.47-3.50 (m, 4H), 5.62 (t, J=8.0Hz, 1H), 6.91 (dd, J=7.6, 1.6 Hz, 1H), 6.96 (ddd, J=7.6, 7.6, 1.6 Hz,1H), 7.08 (dd, J=7.6, 1.6 Hz, 1H), 7.21 (ddd, J=7.6, 7.6, 1.6 Hz, 1H).

46c 4-(2-Cyclooctylphenyl)piperazine-1-carboxylic acid t-butyl ester

A mixture of the 4-(2-cyclooct-1-enylphenyl)piperazine-1-carboxylic acidt-butyl ester (128 mg, 0.345 mmol) produced in Example (46b), 10%palladium on carbon (50 mg, wet) and methanol (8 mL) was stirred for 3hours at atmospheric pressure and room temperature under a hydrogenatmosphere.

The reaction mixture was filtered and the filtrate was concentratedunder reduced pressure. To the resultant residue was added a mixture of10% palladium on carbon (130 mg, wet) and methanol (5mL)-tetrahydrofuran (3 mL), followed by stirring for 1 hour and 30minutes at room temperature under hydrogen atmosphere at 4-5 atm.

The reaction mixture was filtered and the obtained filtrate wasconcentrated under reduced pressure to give a crude product of the titlecompound as a light yellow oil. This product was directly used withoutpurification for the following reaction.

46d 1-(2-Cyclooctylphenyl)piperazine

To a mixture of the crude product of4-(2-cyclooctylphenyl)piperazine-1-carboxylic acid t-butyl esterproduced in Example (46c), 1,2-dichloroethane (2 mL) and water (0.2 mL)was added trifluoroacetic acid (0.500 mL, 6.490 mmol), followed bystirring for 5 hours and 30 minutes at room temperature. Aqueoussolution of potassium carbonate was added to the mixture to make themixture basic. Ethyl acetate was then added thereto and extraction wasperformed three times with ethyl acetate. The organic layers were driedover anhydrous sodium sulfate. The desiccant was filtered off and thefiltrate was concentrated under reduced pressure. The resultant residuewas purified by NH silica gel column chromatography (ethylacetate/heptane) to give 75 mg of the title compound as a light yellowoil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.55-1.72 (m, 14H), 2.83-2.85 (m, 4H),3.02-3.05 (m, 4H), 3.48-3.54 (m, 1H), 7.03-7.14 (m, 3H), 7.19 (dd,J=7.6, 4.4 Hz, 1H).

The 1H of NH could not be identified.

46e 1-(2-Cyclooctylphenyl)-4-isobutylpiperazinee hydrochloride

To a solution of the 1-(2-cyclooctylphenyl)piperazine (7 mg, 0.0257mmol) produced in Example (46d) in tetrahydrofuran (1 mL) were addedisobutyraldehyde (2.4 mg, 0.0334 mmol), sodium triacetoxyborohydride(7.1 mg, 0.0334 mmol) and acetic acid (0.0028 mL, 0.0448 mmol), followedby stirring for 17 hours and 10 minutes at room temperature. Saturatedaqueous solution of sodium hydrogencarbonate was added to the reactionmixture and extraction was performed three times with ethyl acetate. Theorganic layers was concentrated to produce a residue, which was purifiedby NH silica gel column chromatography (ethyl acetate/heptane) to give4.3 mg of 1-(2-cyclooctylphenyl)-4-isobutylpiperazinee as a colorlessoil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.93 (d, J=6.8 Hz, 6H), 1.46-1.88 (m, 15H),2.16 (d, J=7.2 Hz, 2H), 2.55 (brs, 4H), 2.88-2.90 (m, 4H), 3.46-3.52 (m,1H), 7.02-7.13 (m, 3H), 7.18 (dd, J=7.2, 1.6 Hz, 1H).

This compound was dissolved in dichloromethane (1 mL), and then a 4Nsolution of hydrogen chloride in ethyl acetate (0.0066 mL, 0.0262 mmol)was added. The mixture was concentrated under reduced pressure, anddiethyl ether was added to the obtained residue to produce a solid,which was then triturated by sonication. The supernatant diethyl ethersolution was removed and the resulting solid residue was dried underreduced pressure to give 4.4 mg of the title compound as a colorlesssolid.

MS m/e (ESI) 329 (MH⁺).

Example 47 1-Butyl-4-(2-cyclooct-1-enylphenyl)piperazine hydrochloride

To a solution of 1-(2-cyclooct-1-enylphenyl)piperazine (11 mg, 0.0407mmol) produced in Example (46a) in tetrahydrofuran (1 mL) were addedbutyraldehyde (0.0047 mL, 0.0529 mmol), sodium triacetoxyborohydride(11.2 mg, 0.0529 mmol) and acetic acid (0.0044 mL, 0.0773 mmol),followed by stirring for 14 hours and 20 minutes at room temperature.Saturated aqueous solution of sodium hydrogencarbonate was added to thereaction mixture and extraction was performed three times with ethylacetate. The organic layer was concentrated to produce a residue, whichwas purified by NH silica gel column chromatography (ethylacetate/heptane) to give 9.9 mg of1-butyl-4-(2-cyclooct-1-enylphenyl)piperazine as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.93 (t, J=7.6 Hz, 3H), 1.30-1.62 (m, 12H),2.23-2.28 (m, 2H), 2.35-2.39 (m, 2H), 2.54 (brs, 4H), 2.73-2.76 (m, 2H),3.07 (brs, 4H), 5.63 (t, J=8.4 Hz, 1H), 6.92-6.96 (m, 2H), 7.07 (dd,J=7.6, 2.0 Hz, 1H), 7.20 (ddd, J=8.8, 7.6, 2.0 Hz, 1H).

This compound was dissolved in dichloromethane (1 mL) and a 4N solutionof hydrogen chloride in ethyl acetate (0.015 mL, 0.0606 mmol) was added.

The solution was concentrated under reduced pressure, and diethyl etherwas added to the obtained residue to produce a solid, which was thentriturated by sonication. The supernatant diethyl ether solution wasremoved and the resulting solid residue was dried under reduced pressureto give 10.9 mg of the title compound as a light brown solid.

MS m/e (ESI) 327 (MH⁺).

Example 481-(2-Methoxyethyl)-4-[4-(4-methoxypiperidin-1-yl)-2-spiro[5.5]undec-2-en-3-ylphenyl]piperazinehydrochloride

A mixture of1-[4-(4-methoxypiperidin-1-yl)-2-spiro[5.5]undec-2-en-3-yl-phenyl]piperazine(20 mg, 0.0472 mmol) produced in Example (39e), 2-bromoethyl methylether (0.0049 mL, 0.0519 mmol), potassium carbonate (11.1 mg, 0.0803mmol) and acetonitrile (1 mL) was stirred for 5 hours at an externaltemperature of 80° C. Ethyl acetate and brine were added to the reactionmixture and extraction was performed three times with ethyl acetate. Theseparated organic layers were concentrated. The resultant residue waspurified by NH silica gel column chromatography (ethyl acetate/hexane)to give1-(2-methoxyethyl)-4-[4-(4-methoxypiperidin-1-yl)-2-spiro[5.5]undec-2-en-3-ylphenyl]piperazine.

¹H-NMR (400 MHz, CDCl₃) δ: 1.33-1.56 (m, 10H), 1.61-1.75 (m, 4H),1.94-2.05 (m, 4H), 2.42-2.48 (m, 2H), 2.56 (brs, 4H), 2.60 (t, J=5.6 Hz,2H), 2.82 (ddd, J=12.8, 10.0, 2.8 Hz, 2H), 2.95 (brs, 4H), 3.27-3.35 (m,1H), 3.36 (s, 3H), 3.37 (s, 3H), 3.40-3.47 (m, 2H), 3.53 (t, J=5.6 Hz,2H), 5.58 (t, J=1.6 Hz, 1H), 6.70 (d, J=3.2 Hz, 1H), 6.75 (dd, J=8.8,3.2 Hz, 1H), 6.89 (d, J=8.8 Hz, 1H).

This compound was dissolved in dichloromethane (1 mL) and a 4N solutionof hydrogen chloride in ethyl acetate (0.0236 mL, 0.0944 mmol) wasadded. The solution was concentrated, and diethyl ether was added to theobtained residue to produce a solid, which was then triturated bysonication. The supernatant diethyl ether solution was removed and theresulting solid residue was dried under reduced pressure to give 16.8 mgof the title compound as a light yellow solid.

MS m/e (ESI) 482 (MH⁺).

Example 49(R)-1-Butyl-4-[2-(4,4-dimethylcyclohexyl)-4-(3-methoxypiperidin-1-yl)phenyl]piperazinehydrochloride

49a (R)-3-Methoxypiperidine hydrochloride

A mixture of (R)-3-hydroxypiperidine (2.709 g, 19.7 mmol), di-t-butyldicarbonate (4.04 g, 31.5 mmol), dichloromethane (8 mL), triethylamine(5.76 mL, 41.34 mmol) and 4-dimethylaminopyridine (241 mg, 1.97 mmol)was stirred for 4 hours and 20 minutes at room temperature. To thereaction mixture were further added di-t-butyl dicarbonate (1.516 g,11.82 mmol), triethylamine (1.91 mL, 11.82 mmol) and4-dimethylaminopyridine (120 mg, 0.985 mmol), followed by stirring for 4days at room temperature. Aqueous solution of ammonium chloride wasadded to the reaction mixture and extraction was performed twice withdiethyl ether. The separated organic layer was washed with brine andthen dried over anhydrous sodium sulfate. The desiccant was filtered offand the filtrate was concentrated under reduced pressure to give a crudeproduct of (R)-3-hydroxypiperidine-1-carboxylic acid t-butyl ester.

Then, a portion of a mixed solvent of anhydrous tetrahydrofuran (82mL)-dimethylformamide (33 mL) was added to a 60% suspension of sodiumhydride in oil (1.18 g, 29.55 mmol), and the mixture was cooled to anexternal temperature of 0° C. and stirred under a nitrogen atmosphere.The crude product of (R)-3-methoxypiperidine-1-carboxylic acid t-butylester was dissolved in the remainder of the aforementioned mixed solventof anhydrous tetrahydrofuran-dimethylformamide and then slowly added tothe previous mixture. After stirring for 30 minutes under the sameconditions, methyl iodide (1.84 mL, 27.55 mmol) was added to thereaction mixture. It was then slowly warmed to room temperature andfurther stirred for 13 hours. Ice and saturated aqueous solution ofammonium chloride were added to the reaction mixture and extraction wasperformed with diethyl ether. The organic layer was dried over anhydroussodium sulfate. The desiccant was filtered off and the filtrate wasconcentrated under reduced pressure to give a crude product of(R)-3-methoxypiperidine-1-carboxylic acid t-butyl ester. Ethyl acetate(30 mL) was added to the crude product and the mixture was cooled to anexternal temperature of 0° C. and stirred. Then, a 4N solution ofhydrogen chloride in ethyl acetate (147.8 mL, 591 mmol) was graduallyadded and the temperature was raised to room temperature. After stirringfor 4 hours, the mixture was concentrated and dried under reducedpressure to give 4.311 g of a crude product of the title compound as abrown oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.63-1.75 (m, 1H), 1.79-1.98 (m, 2H),2.00-2.11 (m, 1H), 2.99-3.22 (m, 3H), 3.28-3.36 (m, 1H), 3.41 (s, 3H),3.62-3.65 (m, 1H).

The 1H of NH could not be identified.

49b(R)-1-Butyl-4-[2-(4,4-dimethylcyclohexyl)-4-(3-methoxypiperidin-1-yl)phenyl]piperazinehydrochloride

A mixture of1-[4-bromo-2-(4,4-dimethylcyclohexyl)phenyl]-4-butylpiperazine (37.4 mg,0.0918 mmol) produced in Example (21c), (R)-3-methoxypiperidinehydrochloride (16.7 mg, 0.110 mmol) produced in Example 49a,tripotassium phosphate (170 mg, 0.801 mmol), palladium(II) acetate (8.2mg, 0.0365 mmol), tri-t-butylphosphonium tetrafluoroborate (32 mg, 0.110mmol) and xylene (1.5 mL) was stirred for 4 hours and 30 minutes at anexternal temperature of 100° C. under a nitrogen atmosphere. The mixturewas air-cooled to room temperature and then purified by NH silica gelcolumn chromatography (ethyl acetate/hexane) to give 24 mg of(R)-1-butyl-4-[2-(4,4-dimethylcyclohexyl)-4-(3-methoxypiperidin-1-yl)phenyl]piperazineas a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.94 (t, J=7.6 Hz, 3H), 0.97 (s, 3H), 1.01(s, 3H), 1.22-1.72 (m, 14H), 1.82-1.86 (m, 1H), 2.02-2.30 (m, 1H),2.39-2.43 (m, 2H), 2.58 (brs, 4H), 2.66 (dd, J=11.6, 8.4 Hz, 1H), 2.74(ddd, J=11.2, 11.2, 2.8 Hz, 1H), 2.82-2.88 (m, 4H), 2.90-3.00 (m, 1H),3.31-3.38 (m, 1H), 3.39-3.46 (m, 4H), 3.60 (dd, J=11.6, 3.6 Hz, 1H),6.74 (dd, J=8.8, 2.8 Hz, 1H), 6.86 (d, J=2.8 Hz, 1H), 7.06 (d, J=8.8 Hz,1H).

This compound was dissolved in dichloromethane (1 mL), and then a 4Nsolution of hydrogen chloride in ethyl acetate (0.0273 mL, 0.109 mmol)was added.

This solution was concentrated to produce a residue, which wassolidified by addition of diethyl ether, and then triturated bysonication. The supernatant diethyl ether solution was removed and theresulting solid was dried under reduced pressure to give 24.2 mg of thetitle compound as a colorless solid.

MS m/e 442 (ESI) (MH⁺).

Example 50(S)-1-Cyclopropylmethyl-4-[2-(4,4-dimethylcyclohexyl)-4-(3-methoxypiperidin-1-yl)phenyl]piperazinehydrochloride

50a (S)-3-Methoxypiperidine hydrochloride

Reaction was carried out with conditions and procedures similar to thosein Example (49a), using (S)-3-hydroxypiperidine (2 g, 14.5 mmol) as astarting material. The similar treatment was also carried out to give3.237 g of a crude product of the title compound as an orange oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.63-1.77 (m, 1H), 1.78-1.96 (m, 2H),1.98-2.09 (m, 1H), 2.99-3.22 (m, 3H), 3.26-3.34 (m, 1H), 3.41 (s, 3H),3.62-3.65 (m, 1H).

The 1H of NH could not be identified.

50b(S)-4-[2-(4,4-Diethylcyclohexyl)-4-(3-methoxypiperidin-1-yl)phenyl]piperazine-1-carboxylicacid t-butyl ester

A mixture of4-[4-bromo-2-(4,4-dimethylcyclohexyl)phenyl]piperazine-1-carboxylic acidt-butyl ester (153 mg, 0.32 mmol) produced in Example (38c),(S)-3-methoxypiperidine hydrochloride (72.8 mg, 0.48 mmol) produced inExample (50a), sodium t-butoxide (200 mg, 2.08 mmol), palladium(II)acetate (14.4 mg, 0.064 mmol), tri-t-butylphosphonium tetrafluoroborate(57.7 mg, 0.192 mmol) and xylene (4 mL) was stirred for 6 hours and 10minutes at an external temperature of 100° C. under a nitrogenatmosphere. To the reaction mixture were further added sodium t-butoxide(100 mg, 1.04 mmol), palladium(II) acetate (7.2 mg, 0.032 mmol) andtri-t-butylphosphonium tetrafluoroborate (27.9 mg, 0.096 mmol), followedby stirring for 1 hour at an external temperature of 100° C. under anitrogen atmosphere. The reaction mixture was air-cooled to roomtemperature and then purified by NH silica gel column chromatography(ethyl acetate/hexane) to give 59 mg of the title compound as a brownoil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.79 (t, J=7.2 Hz, 3H), 0.81 (t, J=7.2 Hz,3H), 1.14-1.71 (m, 23H), 1.83-1.92 (m, 1H), 2.03-2.10 (m, 1H), 2.65-2.82(m, 10H), 2.92-3.01 (m, 1H), 3.33-3.47 (m, 5H), 3.57-3.62 (m, 1H), 6.74(dd, J=8.8, 3.2 Hz, 1H), 6.85 (d, J=3.2 Hz, 1H), 6.99 (d, J=8.8 Hz, 1H).

50c(S)-1-[2-(4,4-Diethylcyclohexyl)-4-(3-methoxypiperidin-1-yl)phenyl]piperazine

(S)-4-[2-(4,4-Diethylcyclohexyl)-4-(3-methoxypiperidin-1-yl)phenyl]piperazine-1-carboxylicacid t-butyl ester (59 mg, 0.1148 mmol) produced in Example (50b) wasdissolved in a mixed solvent of dichloromethane (0.7 mL)-water (1 drop).Trifluoroacetic acid (0.177 mL, 2.296 mmol) was added thereto followedby stirring for 15 hours and 20 minutes under the same conditions.Aqueous solution of potassium carbonate was added to the reactionmixture to make the mixture basic. The mixture was then extracted withethyl acetate. The separated organic layer was concentrated underreduced pressure to give a crude product of(S)-1-[2-(4,4-dimethylcyclohexyl)-4-(3-methoxypiperidin-1-yl)phenyl]piperazineas a brown oil. This was directly used without purification for thefollowing reaction.

50d(S)-1-Cyclopropylmethyl-4-[2-(4,4-dimethylcyclohexyl)-4-(3-methoxypiperidin-1-yl)phenyl]piperazinehydrochloride

To a solution of the crude product of(S)-1-[2-(4,4-dimethylcyclohexyl)-4-(3-methoxypiperidin-1-yl)phenyl]piperazineproduced in Example (50c) in tetrahydrofuran (1 mL) were addedcyclopropanecarbaldehyde (0.0056 mL, 0.07462 mmol), sodiumtriacetoxyborohydride (16 mg, 0.07462 mmol) and acetic acid (0.0062 mL,0.1091 mmol), followed by stirring for 5 hours at room temperature.

After the reaction, saturated aqueous solution of sodiumhydrogencarbonate was added to the reaction mixture and extraction wasperformed three times with ethyl acetate. The separated organic layerswere concentrated. The resultant residue was purified by NH silica gelcolumn chromatography (ethyl acetate/heptane) to give(S)-1-cyclopropylmethyl-4-[2-(4,4-dimethylcyclohexyl)-4-(3-methoxypiperidin-1-yl)phenyl]piperazine.

¹H-NMR (400 MHz, CDCl₃) δ: 0.23-0.27 (m, 2H), 0.52-0.57 (m, 2H), 0.79(t, J=7.6 Hz, 3H), 0.81 (t, J=7.6 Hz, 3H), 0.86-0.97 (m, 1H), 1.14-1.72(m, 14H), 1.84-1.91 (m, 1H), 2.04-2.10 (m, 1H), 2.33 (d, J=6.8 Hz, 2H),2.63-2.77 (m, 6H), 2.84-2.99 (m, 5H), 3.33-3.45 (m, 5H), 3.58-3.62 (m,1H), 6.74 (dd, J=8.4, 2.8 Hz, 1H), 6.85 (d, J=2.8 Hz, 1H), 7.08 (d,J=8.4 Hz, 1H).

This compound was dissolved in dichloromethane (1 mL) and a 4N solutionof hydrogen chloride in ethyl acetate (0.0287 mL, 0.1148 mmol) wasadded. This solution was concentrated to produce a residue, which wassolidified by addition of diethyl ether, and was then triturated bysonication. The supernatant diethyl ether solution was removed and theresulting solid was dried under reduced pressure to give 17.5 mg of thetitle compound as a brown solid.

MS m/e 468 (ESI) (MH⁺).

Example 511-Cyclopentyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

A mixture of 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (25mg, 0.0832 mmol) produced in Example (8b), cyclopentanone (9.1 mg, 0.108mmol), sodium triacetoxyborohydride (33.5 mg, 0.158 mmol) and aceticacid (0.009 mL, 0.158 mmol) was stirred for 1 hour and 40 minutes atroom temperature. Saturated aqueous solution of sodium hydrogencarbonatewas added to the reaction mixture and extraction was performed threetimes with ethyl acetate. The organic layer was concentrated to producea residue, which was purified by NH silica gel column chromatography(ethyl acetate/hexane) to give1-cyclopentyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine as acolorless oil.

δ: 0.92 (s, 6H), 1.13 (s, 6H), 1.16-1.36 (m, 6H), 1.39-1.51 (m, 4H),1.66-1.76 (m, 2H), 1.86-1.96 (m, 2H), 2.48-2.58 (m, 1H), 2.67 (brs, 4H),2.89-2.98 (m, 4H), 3.52-3.61 (m, 1H), 7.04-7.14 (m, 3H), 7.21 (d, J=8.8Hz, 1H).

This compound was dissolved in dichloromethane (1 mL), and then a 4Nsolution of hydrogen chloride in ethyl acetate (0.0416 mL, 0.166 mmol)was added. The solution was concentrated, and then diethyl ether wasadded to the obtained residue to produce a solid, which was thentriturated by sonication. The supernatant diethyl ether solution wasremoved and the resulting solid was dried under reduced pressure to give24.3 mg of the title compound as a colorless solid.

MS m/e 369 (ESI) (MH⁺).

Example 521-(2-Methylsulfanylethyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

A mixture of the 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine(100 mg, 0.333 mmol) produced in Example (8b), 2-chloroethyl methylsulfide (38.7 mg, 0.349 mmol), potassium carbonate (78.2 mg, 0.566 mmol)and acetonitrile (2 mL) was stirred for 8 hours and 30 minutes at anexternal temperature of 80° C. The reaction mixture was concentrated andthe resultant residue was purified by NH silica gel columnchromatography (ethyl acetate/heptane) to give 88 mg of1-(2-methylsulfanylethyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazineas a colorless solid.

¹H-NMR (400 MHz, CDCl₃) δ: 0.93 (s, 6H), 1.12-1.46 (m, 12H), 2.14-2.18(m, 2H), 2.55-2.75 (m, 9H), 2.93 (t, J=4.8 Hz, 4H), 3.48-3.60 (m, 1H),7.05-7.17 (m, 3H), 7.23 (dd, J=7.6, 2.8 Hz, 1H).

After dissolving1-(2-methylsulfanylethyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine(22 mg, 0.0588 mmol) in dichloromethane (1.5 mL), a 4N solution ofhydrogen chloride in ethyl acetate (0.0294 mL, 0.1175 mmol) was added.The solution was concentrated, diethyl ether was added to the obtainedresidue to produce a solid, and the supernatant diethyl ether solutionwas removed. The resultant solid was dried under reduced pressure togive 14 mg of the title compound as a colorless solid.

MS m/e (ESI) 375 (MH⁺).

Example 531-(2-Cyclopropylethyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

To a solution of cyclopropylacetaldehyde in 1,2-dichloroethane (0.29 M,5 mL) were added 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine(25 mg, 0.0832 mmol) produced in Example (8b), sodiumtriacetoxyborohydride (22.9 mg, 0.108 mmol) and acetic acid (0.009 mL,0.158 mmol), followed by stirring for 20 minutes at room temperature.Saturated aqueous solution of sodium hydrogencarbonate was added to thereaction mixture and extraction was performed twice with ethyl acetate.The organic layer was concentrated and the resultant residue waspurified by NH silica gel column chromatography (ethyl acetate/heptane)to give 20.9 mg of1-(2-cyclopropylethyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazineas a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.05-0.08 (m, 2H), 0.42-0.46 (m, 2H),0.63-0.73 (m, 1H), 0.93 (s, 6H), 1.10-1.48 (m, 14H), 2.50-2.53 (m, 2H),2.61 (brs, 4H), 2.92 (dd, J=4.4, 4.4 Hz, 4H), 3.52-3.63 (m, 1H),7.05-7.17 (m, 3H), 7.22 (dd, J=7.2, 1.2 Hz, 1H).

This compound was dissolved in dichloromethane (1 mL) and a 4N solutionof hydrogen chloride in ethyl acetate (0.0283 mL, 0.113 mmol) was added.The solution was concentrated, and diethyl ether was added to theobtained residue to produce a solid, which was then triturated bysonication. The supernatant diethyl ether solution was removed and theresulting solid was dried under reduced pressure to give 15.6 mg of thetitle compound as a colorless solid.

MS m/e 369 (ESI) (MH⁺).

Example 541-Isobutyl-4-[2-(3,3,4,4-tetramethylcyclopent-1-enyl)phenyl]piperazinehydrochloride

54a Trifluoromethanesulfonic acid 3,3,4,4-tetramethylcyclopent-1-enylester

A solution of 3,3,4,4-tetramethylcyclopentanone (860 mg, 6.12 mmol) inanhydrous tetrahydrofuran (10 mL) was cooled to an internal temperatureof −72° C. under a nitrogen atmosphere. To this stirred solution wasslowly added dropwise bis(trimethylsilyl)amide lithium (1M solution intetrahydrofuran, 7.34 mL, 7.34 mmol) over a period of 30 minutes. Afterstirring for 30 minutes under the same conditions, a solution ofN-phenylbis(trifluoromethanesulfonimide) (2.41 g, 6.73 mmol) inanhydrous tetrahydrofuran (18 mL) was added to the reaction mixture, andstirring was continued for 16 hours and 30 minutes while graduallyheating to room temperature. Ethyl acetate and 5N hydrochloric acid wereadded to the reaction mixture and extraction was performed three timeswith ethyl acetate. The separated organic layers were combined andwashed 3 times with 5N hydrochloric acid. The obtained organic layer wasdried over anhydrous sodium sulfate. The desiccant was filtered off andthe filtrate was concentrated under reduced pressure. The resultantresidue was purified by silica gel column chromatography (ethylacetate/heptane) to give 992 mg of the title compound as a colorlessoil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.97 (s, 3H), 0.98 (s, 3H), 1.017 (s, 3H),1.023 (s, 3H), 2.39 (d, J=1.6 Hz, 2H), 5.39 (t, J=1.6 Hz, 1H).

54b 1-Nitro-2-(3,3,4,4-tetramethylcyclopent-1-enyl)benzene

A mixture of the trifluoromethanesulfonic acid3,3,4,4-tetramethylcyclopent-1-enyl ester (992 mg, 3.64 mmol) producedin Example (54a), 2-nitrophenylboronic acid (729 mg, 4.37 mmol),tetrakis(triphenylphosphine)palladium(0) (219 mg, 0.189 mmol), 2Naqueous solution of sodium carbonate (3.64 mL), toluene (12.5 mL) andethanol (6.3 mL) was stirred for 6 hours at an external temperature of90° C. under a nitrogen atmosphere. The reaction mixture was air-cooledto room temperature, and then ethyl acetate and brine were added andextraction was performed twice with ethyl acetate. The separated organiclayer was dried over anhydrous sodium sulfate. The desiccant wasfiltered off and the filtrate was concentrated under reduced pressure.The resultant residue was purified by silica gel column chromatography(ethyl acetate/heptane) to give 891 mg of the title compound as a lightbrown oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.98 (s, 6H), 1.02 (s, 6H), 2.40 (d, J=1.6Hz, 2H), 5.59 (t, J=1.6 Hz, 1H), 7.25-7.34 (m, 2H), 7.47 (ddd, J=8.0,7.2, 1.2 Hz, 1H), 7.70 (dd, J=8.0, 1.2 Hz, 1H).

54c 2-(3,3,4,4-Tetramethylcyclopent-1-enyl)phenylamine

To a mixture of 1-nitro-2-(3,3,4,4-tetramethylcyclopent-1-enyl)benzene(441 mg, 1.8 mmol) produced in Example (54b), ethanol (10 mL) and water(3.3 mL) were added ammonium chloride (48.1 mg, 0.899 mmol) and ironpowder (352 mg, 6.3 mmol), followed by stirring for 5 hours at anexternal temperature of 90° C. After further adding ammonium chloride(9.63 mg, 0.18 mmol) and iron powder (100 mg, 1.8 mmol) to the reactionmixture, stirring was continued for 12 hours at an external temperatureof 75° C. The reaction mixture was cooled to room temperature and thenfiltered. The filtrate was concentrated under reduced pressure, and theresultant residue was purified by silica gel column chromatography(ethyl acetate/heptane) to give 331 mg of the title compound as acolorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.99 (s, 6H), 1.02 (s, 6H), 2.54 (d, J=1.2Hz, 2H), 3.93 (brs, 2H), 5.74 (t, J=1.2 Hz, 1H), 6.68-6.74 (m, 2H),6.99-7.06 (m, 2H).

54d 1-[2-(3,3,4,4-Tetramethylcyclopent-1-enyl)phenyl]piperazine

A mixture of 2-(3,3,4,4-tetramethylcyclopent-1-enyl)phenylamine (331 mg,1.54 mmol) produced in Example (54c), 1,2-dichlorobenzene (4.7 mL) andbis(2-chloroethyl)amine hydrochloride (330 mg, 1.85 mmol) was stirredfor 9 hours at an external temperature of 200° C. under a nitrogenatmosphere. During the reaction, a nitrogen stream was blown into thereactor several times to remove the hydrogen chloride gas in thereactor. The reaction mixture was air-cooled to room temperature, andthen aqueous solution of potassium carbonate, ethyl acetate and methanolwere added and extraction was performed three times with ethyl acetate.The obtained organic layers were dried over anhydrous sodium sulfate.The desiccant was filtered off and the filtrate was concentrated underreduced pressure. The obtained residue was purified by NH silica gelcolumn chromatography (ethyl acetate/heptane) to give 223 mg of thetitle compound as a brown oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.97 (s, 6H), 1.00 (s, 6H), 2.60 (d, J=1.4Hz, 2H), 2.90-2.96 (m, 4H), 2.98-3.02 (m, 4H), 6.00 (t, J=1.4 Hz, 1H),6.94-6.99 (m, 2H), 7.15-7.19 (m, 2H).

The 1H of NH could not be identified.

54e1-Isobutyl-4-[2-(3,3,4,4-tetramethylcyclopent-1-enyl)phenyl]piperazinehydrochloride

To a solution of the1-[2-(3,3,4,4-tetramethylcyclopent-1-enyl)phenyl]piperazine (20 mg,0.0703 mmol) produced in Example (54d) in tetrahydrofuran (1 mL) wereadded isobutyraldehyde (6.6 mg, 0.0914 mmol), sodiumtriacetoxyborohydride (19.4 mg, 0.0914 mmol) and acetic acid (0.0076 mL,0.134 mmol), followed by stirring for 4 hours at room temperature. Afterfurther adding isobutyraldehyde (6.6 mg, 0.0914 mmol), sodiumtriacetoxyborohydride (19.4 mg, 0.0914 mmol) and acetic acid (0.0076 mL,0.134 mmol) to the mixture, stirring was continued for 3 hours at roomtemperature. Saturated aqueous solution of sodium hydrogencarbonate wasadded to the reaction mixture and extraction was performed three timeswith ethyl acetate. The obtained organic layers were concentrated andthe resultant residue was purified by NH silica gel columnchromatography (ethyl acetate/heptane) to give 4.3 mg of1-isobutyl-4-[2-(3,3,4,4-tetramethylcyclopent-1-enyl)phenyl]piperazineas a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.92 (d, J=6.4 Hz, 6H), 0.97 (s, 6H), 1.00(s, 6H), 1.76-1.86 (m, 1H), 2.14 (d, J=7.6 Hz, 2H), 2.52 (brs, 4H), 2.59(d, J=1.6 Hz, 2H), 2.98 (brs, 4H), 5.98 (t, J=1.6 Hz, 1H), 6.92-7.00 (m,2H), 7.14-7.18 (m, 2H).

This compound was dissolved in dichloromethane (1 mL), and a 4N solutionof hydrogen chloride in ethyl acetate (0.0063 mL, 0.0253 mmol) wasadded. The solution was concentrated under reduced pressure, and diethylether was added to the obtained residue to produce a solid, which wasthen triturated by sonication. The supernatant diethyl ether solutionwas removed and the resulting solid was dried under reduced pressure togive 4.8 mg of the title compound as a colorless solid.

MS m/e (ESI) 341 (MH⁺).

Example 551-Propyl-4-[2-(3,3,4,4-tetramethylcyclopentyl)phenyl]piperazinehydrochloride

55a 2-(3,3,4,4-Tetramethylcyclopentyl)phenylamine

A mixture of 1-nitro-2-(3,3,4,4-tetramethylcyclopent-1-enyl)benzene (450mg, 1.83 mmol) produced in Example (54b), 10% palladium on carbon (200mg, wet) and methanol (40 mL) was stirred for 3 hours and 30 minutes atatmospheric pressure and room temperature under a hydrogen atmosphere.The reaction mixture was filtered, 10% palladium on carbon (200 mg,hydrous) and a 4N solution of hydrogen chloride in ethyl acetate (0.915mL, 3.66 mmol) were added to the filtrate, and then stirring wascontinued for 13 hours and 30 minutes at room temperature andatmospheric pressure under a hydrogen atmosphere. The reaction mixturewas filtered and the filtrate was concentrated under reduced pressure.The resultant residue was purified by silica gel column chromatography(ethyl acetate/heptane) to give 295 mg of the title compound as a brownoil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.96 (s, 6H), 0.97 (s, 6H), 1.80 (dd, J=13.2,8.8 Hz, 2H), 2.01 (dd, J=13.2, 9.2 Hz, 2H), 3.15-3.36 (m, 3H), 6.67 (dd,J=7.6, 1.2 Hz, 1H), 6.76 (ddd, J=7.6, 7.6, 1.2 Hz, 1H), 7.00 (ddd,J=7.6, 7.6, 1.2 Hz, 1H), 7.23 (d, J=7.6 Hz, 1H).

55b 1-[2-(3,3,4,4-Tetramethylcyclopentyl)phenyl]piperazine

A mixture of 2-(3,3,4,4-tetramethylcyclopentylphenyl)amine (295 mg, 1.36mmol) produced in Example (55a), 1,2-dichlorobenzene (3.84 mL) andbis(2-chloroethyl)amine hydrochloride (291 mg, 1.63 mmol) was stirredfor 5 hours and 30 minutes at an external temperature of 200° C. under anitrogen atmosphere. During the reaction, a nitrogen stream was blowninto the reactor to remove the hydrogen chloride gas in the reactor. Thereaction mixture was cooled to room temperature, and then aqueoussolution of potassium carbonate, ethyl acetate and methanol were addedand extraction was performed three times with ethyl acetate. Theobtained organic layers were dried over anhydrous sodium sulfate. Thedesiccant was filtered off and the filtrate was concentrated underreduced pressure. The resultant residue was purified by NH silica gelcolumn chromatography (ethyl acetate/heptane) to give 207 mg of thetitle compound as a brown oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.98 (s, 6H), 1.01 (s, 6H), 1.68 (dd, J=13.2,9.2 Hz, 2H), 1.96 (dd, J=13.2, 9.2 Hz, 2H), 2.80-2.87 (m, 4H), 2.98-3.04(m, 4H), 3.94 (tt, J=9.2, 9.2 Hz, 1H), 7.05-7.16 (m, 3H), 7.37 (dd,J=7.2, 1.6 Hz, 1H).

The 1H of NH could not be identified.

55c 1-Propyl-4-[2-(3,3,4,4-tetramethylcyclopentyl)phenyl]piperazinehydrochloride

To a solution of the1-[2-(3,3,4,4-tetramethylcyclopentyl)phenyl]piperazine (20 mg, 0.0698mmol) produced in Example (55b) in tetrahydrofuran (1 mL) were addedpropionaldehyde (0.0065 mL, 0.0908 mmol), sodium triacetoxyborohydride(19.2 mg, 0.0908 mmol) and acetic acid (0.0076 mL, 0.133 mmol), followedby stirring for 3 hours at room temperature. After further addingpropionaldehyde (0.0065 mL, 0.0908 mmol), sodium triacetoxyborohydride(19.2 mg, 0.0908 mmol) and 1,2-dichloroethane (1 mL) to the reactionmixture, stirring was continued for 18 hours and 30 minutes at roomtemperature. Saturated aqueous solution of sodium hydrogencarbonate wasadded to the reaction mixture and extraction was performed three timeswith ethyl acetate. The obtained organic layers were concentrated. Theresultant residue was purified by NH silica gel column chromatography(ethyl acetate/heptane) to give 1.2 mg of1-propyl-4-[2-(3,3,4,4-tetramethylcyclopentyl)phenyl]piperazine as acolorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.94 (t, J=7.2 Hz, 3H), 0.98 (s, 6H), 1.01(s, 6H), 1.50-1.59 (m, 2H), 1.68 (dd, J=13.2, 9.6 Hz, 2H), 1.96 (dd,J=13.2, 9.6 Hz, 2H), 2.36-2.40 (m, 2H), 2.61 (brs, 4H), 2.91-2.93 (m,4H), 3.92 (tt, J=9.6, 9.6 Hz, 1H), 7.06-7.15 (m, 3H), 7.36 (d, J=7.2 Hz,1H).

This compound was dissolved in dichloromethane (1 mL), and a 4N solutionof hydrogen chloride in ethyl acetate (0.0018 mL, 0.0730 mmol) wasadded. This solution was concentrated under reduced pressure, anddiethyl ether was added to the obtained residue to produce a solid,which was then triturated by sonication. The solid was filtered and thendried under reduced pressure to give 1.7 mg of the title compound as acolorless solid.

MS m/e (ESI) 329 (MH⁺).

Example 564-[4-(4-Pentylpiperazin-1-yl)-3-spiro[2.5]oct-5-en-6-ylphenyl]morpholinehydrochloride

56a4-(4-Morpholin-4-yl-2-spiro[2.5]oct-5-en-6-ylphenyl)piperazine-1-carboxylicacid t-butyl ester

A mixture of4-(4-morpholin-4-yl-2-trifluoromethanesulfonyloxyphenyl)piperazine-1-carboxylicacid t-butyl ester (1.49 g, 3.01 mmol), 1,2-dimethoxyethane (15 mL),water (1 mL),4,4,5,5-tetramethyl-2-spiro[2.5]oct-5-en-6-yl-[1,3,2]dioxaborolane (1.13g, 4.82 mmol) produced in Example (34b),tetrakis(triphenylphosphine)palladium(0) (278 mg, 0.241 mmol) andtripotassium phosphate (1.23 g, 5.78 mmol) was stirred for 13 hours and20 minutes at an external temperature of 80-90° C. under a nitrogenatmosphere. Ethyl acetate and brine were added to the reaction mixtureand extraction was performed three times with ethyl acetate. The organiclayer was dried over anhydrous sodium sulfate, the desiccant wasfiltered off and the filtrate was concentrated under reduced pressure.The residue was purified by NH silica gel column chromatography (ethylacetate/hexane) to give 1.23 g of the title compound as a colorlesssolid.

56b 4-(4-Piperazin-1-yl-3-spiro[2.5]oct-5-en-6-ylphenyl)morpholine

Reaction was conducted in a manner similar to Example (4f), using4-(4-morpholin-4-yl-2-spiro[2.5]oct-5-en-6-ylphenyl)piperazine-1-carboxylicacid t-butyl ester (1.23 g, 2.71 mmol) produced in Example (56a) as astarting material, and then treatment was carried out in a similarmanner to give 1.30 g of the title compound as a light brown solid.

¹H-NMR (400 MHz, CDCl₃) δ: 0.32-0.40 (m, 4H), 1.50 (t, J=6.4 Hz, 2H),2.02-2.06 (m, 2H), 2.53 (d, J=1.6 Hz, 2H), 3.05-3.18 (m, 12H), 3.85 (t,J=4.8 Hz, 4H), 5.69-5.73 (m, 1H), 6.74 (d, J=2.4 Hz, 1H), 6.78 (dd,J=9.6, 2.4 Hz, 1H), 6.94 (d, J=9.6 Hz, 1H).

The 1H of NH could not be identified.

56c4-[4-(4-Pentylpiperazin-1-yl)-3-spiro[2.5]oct-5-en-6-ylphenyl]morpholinehydrochloride

To a solution of4-(4-piperazin-1-yl-3-spiro[2.5]oct-5-en-6-ylphenyl)morpholine (330 mg,0.933 mmol) produced in Example (56b) in tetrahydrofuran (10 mL) wereadded valeraldehyde (104.5 mg, 1.214 mmol), sodium triacetoxyborohydride(257.2 mg, 1.214 mmol) and acetic acid (0.1015 mL, 1.774 mmol), followedby stirring for 1 hour and 30 minutes at room temperature. Saturatedaqueous solution of sodium hydrogencarbonate was added to the reactionmixture and extraction was performed three times with ethyl acetate. Theobtained organic layer was dried over anhydrous sodium sulfate. Thedesiccant was filtered off and the filtrate was concentrated underreduced pressure. The resultant residue was purified by NH silica gelcolumn chromatography (ethyl acetate/hexane) to give 269 mg of the titlecompound as a colorless solid.

¹H-NMR (400 MHz, CDCl₃) δ: 0.33-0.38 (m, 4H), 0.91 (t, J=6.8 Hz, 3H),1.24-1.38 (m, 4H), 1.48-1.55 (m, 4H), 2.02-2.05 (m, 2H), 2.34-2.38 (m,2H), 2.47-2.62 (m, 6H), 2.99 (brs, 4H), 3.10-3.12 (m, 4H), 3.84-3.86 (m,4H), 5.69-5.73 (m, 1H), 6.73-6.77 (m, 2H), 6.93 (d, J=8.4 Hz, 1H).

After dissolving 125 mg of this compound in dichloromethane (4 mL), a 4Nsolution of hydrogen chloride in ethyl acetate (0.147 mL, 0.590 mmol)was added. The solution was concentrated under reduced pressure, anddiethyl ether was added to the obtained residue to produce a solid,which was then triturated by sonication. The solid was filtered anddried under reduced pressure to give 120 mg of the title compound as acolorless solid.

MS m/e (ESI) 424 (MH⁺).

Example 571-[4-Bromo-2-(4,4-dimethylcyclohexyl)phenyl]-4-butylpiperazine

57a 1-[4-Bromo-2-(4,4-dimethylcyclohexyl)phenyl]piperazine

A mixture of4-[4-bromo-2-(4,4-dimethylcyclohexyl)phenyl]piperazine-1-carboxylic acidt-butyl ester (1.5 g, 3.32 mmol) produced in Example (3e),trifluoroacetic acid (3 mL, 38.7 mmol) and dichloromethane (6 mL) wasstirred for 2 hours and 30 minutes at room temperature. Saturatedaqueous solution of sodium carbonate was added to the reaction mixtureand extraction was performed with ethyl acetate. The separated organiclayer was washed with water and brine in that order and then dried overanhydrous sodium sulfate. The desiccant was filtered off and thefiltrate was concentrated under reduced pressure. The residue was driedunder reduced pressure to give 1.21 g of a crude product of the titlecompound as a brown oil.

57b 1-[4-Bromo-2-(4,4-dimethylcyclohexyl)phenyl]-4-butylpiperazine

To a mixture of the crude product of1-[4-bromo-2-(4,4-dimethylcyclohexyl)phenyl]piperazine produced inExample (57a) (1.21 g), butyraldehyde (0.35 mL, 3.98 mmol), acetic acid(0.1 mL, 3.32 mmol) and tetrahydrofuran (8 mL) was added sodiumtriacetoxyborohydride (1.1 g, 4.98 mmol), followed by stirring for 2hours and 10 minutes at room temperature. Saturated aqueous solution ofsodium hydrogencarbonate was added to the reaction mixture andextraction was performed with ethyl acetate. The separated organic layerwas washed with water and brine in that order and then dried overanhydrous sodium sulfate. The desiccant was filtered off and thefiltrate was concentrated under reduced pressure. The resultant residuewas purified by NH silica gel column chromatography (ethylacetate/hexane) to give 901 mg of the title compound as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.94 (t, J=7.2 Hz, 3H), 0.97 (s, 3H), 1.01(s, 3H), 1.24-1.60 (m, 12H), 2.38-2.44 (m, 2H), 2.59 (brs, 4H),2.82-2.97 (m, 5H), 6.97 (d, J=8.8 Hz, 1H), 7.24 (dd, J=8.8, 2.4 Hz, 1H),7.33 (d, J=2.4 Hz, 1H).

Example 581-[4-(4-Butylpiperazin-1-yl)-3-(4,4-dimethylcyclohexyl)phenyl]piperidine-4-carbonitrilehydrochloride

A mixture of1-[4-bromo-2-(4,4-dimethylcyclohexyl)phenyl]-4-butylpiperazine (50 mg,0.123 mmol) produced in Example (57b), piperidine-4-carbonitrilehydrochloride (27 mg, 0.185 mmol), sodium t-butoxide (47 mg, 0.492mmol), palladium(II) acetate (3 mg, 0.0123 mmol), tri-t-butylphosphoniumtetrafluoroborate (11 mg, 0.0369 mmol) and xylene (1 mL) was stirred for1 hour at an external temperature of 100° C.

The reaction mixture was purified by NH silica gel column chromatography(ethyl acetate/hexane) to give 32 mg of1-[4-(4-butylpiperazine-1-yl)-3-(4,4-dimethylcyclohexyl)phenyl]piperidine-4-carbonitrileas a colorless solid.

¹H-NMR (400 MHz, CDCl₃) δ: 0.94 (t, J=7.6 Hz, 3H), 0.97 (s, 3H), 1.01(s, 3H), 1.24-1.64 (m, 12H), 1.95-2.13 (m, 4H), 2.36-2.46 (m, 2H), 2.59(brs, 4H), 2.72-2.79 (m, 1H), 2.86 (brs, 4H), 2.91-3.05 (m, 3H),3.31-3.41 (m, 2H), 6.72 (dd, J=8.8, 2.8 Hz, 1H), 6.84 (d, J=2.8 Hz, 1H),7.07 (d, J=8.8 Hz, 1H).

This compound was dissolved in ethyl acetate and a 4N solution ofhydrogen chloride in ethyl acetate was added. The mixture wasconcentrated under reduced pressure. Hexane was added to the residue toproduce a solid, which was then triturated by sonication. Thesupernatant hexane solution was removed and the solid was dried to give25 mg of the title compound as a colorless solid.

MS m/e (ESI) 437 (MH⁺).

Example 591-[4-Azetidin-1-yl-2-(4,4-dimethylcyclohexyl)phenyl]-4-butylpiperazinehydrochloride

A mixture of1-[4-bromo-2-(4,4-dimethylcyclohexyl)phenyl]-4-butylpiperazine (50 mg,0.123 mmol) produced in Example (57b), azetidine hydrochloride (17 mg,0.185 mmol), sodium t-butoxide (47 mg, 0.492 mmol), palladium(II)acetate (3 mg, 0.0123 mmol), tri-t-butylphosphonium tetrafluoroborate(11 mg, 0.0369 mmol) and xylene (1 mL) was stirred for 3 hours at anexternal temperature of 100° C. Water was added to the reaction mixtureand extraction was performed with ethyl acetate. The separated organiclayer was filtered through Celite. The solvent was distilled off bynitrogen stream to the filtrate. The resultant residue was purified byNH silica gel column chromatography (ethyl acetate/hexane) to give1-[4-azetidin-1-yl-2-(4,4-dimethylcyclohexyl)phenyl]-4-butylpiperazineas a colorless solid.

¹H-NMR (400 MHz, CDCl₃) δ: 0.94 (t, J=7.6 Hz, 3H), 0.96 (s, 3H), 1.00(s, 3H), 1.25-1.66 (m, 12H), 2.32 (quintet, J=7.2 Hz, 2H), 2.37-2.42 (m,2H), 2.56 (brs, 4H), 2.84 (brs, 4H), 2.90-3.00 (m, 1H), 3.85 (t, J=7.2Hz, 4H), 6.27 (dd, J=8.4, 2.8 Hz, 1H), 6.32 (d, J=2.8 Hz, 1H), 7.06 (d,J=8.4 Hz, 1H).

This compound was dissolved in ethyl acetate and a 4N solution ofhydrogen chloride in ethyl acetate was added. The mixture was thenconcentrated under reduced pressure. Hexane was added to the residue toproduce a solid, which was then triturated by sonication. Thesupernatant hexane solution was removed and the resulting solid wasdried to give 20 mg of the title compound as a colorless solid.

MS m/e (ESI) 384 (MH⁺).

Example 601-[4-(4-Butylpiperazin-1-yl)-3-(4,4-dimethylcyclohexyl)phenyl]azepanehydrochloride

A mixture of1-[4-bromo-2-(4,4-dimethylcyclohexyl)phenyl]-4-butylpiperazine (50 mg,0.123 mmol) produced in Example (57b), hexamethyleneimine (18 mg, 0.185mmol), sodium t-butoxide (30 mg, 0.308 mmol), palladium(II) acetate (3mg, 0.0123 mmol), tri-t-butylphosphonium tetrafluoroborate (11 mg,0.0369 mmol) and xylene (1 mL) was stirred for 3 hours at an externaltemperature of 100° C. Water was added to the reaction mixture andextraction was performed with ethyl acetate. The separated organic layerwas filtered through Celite. The solvent was distilled off by nitrogenstream to the filtrate. The resultant residue was purified by NH silicagel column chromatography (ethyl acetate/hexane) to give1-[4-(4-butylpiperazine-1-yl)-3-(4,4-dimethylcyclohexyl)phenyl]azepaneas a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 0.94 (t, J=7.6 Hz, 3H), 0.97 (s, 3H), 1.01(s, 3H), 1.28-1.85 (m, 20H), 2.36-2.44 (m, 2H), 2.58 (brs, 4H),2.77-3.02 (m, 5H), 3.35-3.46 (m, 4H), 6.50 (dd, J=8.8, 3.2 Hz, 1H), 6.55(d, J=3.2 Hz, 1H), 7.06 (d, J=8.8 Hz, 1H).

This compound was dissolved in ethyl acetate, and a 4N solution ofhydrogen chloride in ethyl acetate was added. The mixture wasconcentrated under reduced pressure. Hexane was added to the residue toproduce a solid, which was then triturated by sonication. Thesupernatant hexane solution was removed and the resulting solid wasdried to give 36 mg of the title compound as a colorless solid.

MS m/e (ESI) 426 (MH⁺).

Example 61cis-4-[4-(4-Cyclobutylmethylpiperazin-1-yl)-3-(4,4-dimethylcyclohexyl)phenyl]-2,6-dimethylmorpholinehydrochloride

61acis-4-[2-(4,4-Dimethylcyclohexyl)-4-(2,6-dimethylmorpholin-4-yl)phenyl]piperazine-1-carboxylicacid t-butyl ester

A mixture of the4-[4-bromo-2-(4,4-dimethylcyclohexyl)phenyl]piperazine-1-carboxylic acidt-butyl ester (700 mg, 1.55 mmol) produced in Example (3e),cis-2,6-dimethylmorpholine (268 mg, 2.33 mmol), sodium t-butoxide (372mg, 3.88 mmol), palladium(II) acetate (35 mg, 0.155 mmol),tri-t-butylphosphonium tetrafluoroborate (135 mg, 0.465 mmol) and xylene(7 mL) was stirred for 2 hours at an external temperature of 100° C.under a nitrogen atmosphere. The reaction mixture was air-cooled to roomtemperature, and then the insoluble matters were filtered off, water wasadded to the obtained filtrate and extraction was performed with ethylacetate. The separated organic layer was washed with water and brine inthat order and then dried over anhydrous sodium sulfate. The desiccantwas filtered off and the filtrate was concentrated under reducedpressure. The resultant residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give 648 mg of the titlecompound as yellow crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 0.97 (s, 3H), 1.02 (s, 3H), 1.25 (s, 3H),1.27 (s, 3H), 1.28-1.70 (m, 17H), 2.39 (dd, J=12.0, 10.4 Hz, 2H),2.65-2.85 (m, 4H), 2.93-3.04 (m, 1H), 3.38 (d, J=10.4, 2H), 3.49 (brs,4H), 3.75-3.88 (m, 2H), 6.70 (dd, J=8.8, 2.8 Hz, 1H), 6.82 (d, J=2.8 Hz,1H), 7.01 (d, J=8.8 Hz, 1H).

61bcis-4-[3-(4,4-Dimethylcyclohexyl)-4-piperazin-1-ylphenyl]-2,6-dimethylmorpholine

Tocis-4-[2-(4,4-dimethylcyclohexyl)-4-(2,6-dimethylmorpholin-4-yl)phenyl]piperazine-1-carboxylicacid t-butyl ester (648 mg, 1.33 mmol) produced in Example (61a) wasadded a mixed solvent of ethyl acetate (5 mL)-dichloromethane (1 mL),followed by stirring at room temperature under a nitrogen atmosphere. A4N solution of hydrogen chloride in ethyl acetate (5 mL, 20 mmol) wasadded dropwise thereto, followed by stirring for 17 hours under the sameconditions. Saturated aqueous solution of sodium carbonate was added tothe reaction mixture to make the mixture basic. Dichloromethane andwater were added thereto and extraction was performed withdichloromethane. The separated organic layer was washed with brine andthen dried over anhydrous sodium sulfate. The desiccant was filtered offand the filtrate was concentrated under reduced pressure. The resultantresidue was purified by NH silica gel column chromatography (ethylacetate/hexane) to give 451 mg of the title compound as light yellowcrystals.

¹H-NMR (400 MHz, CDCl₃) δ: 0.97 (s, 3H), 1.03 (s, 3H), 1.25 (s, 3H),1.27 (s, 3H), 1.40-1.70 (m, 8H), 2.39 (dd, J=11.6, 10.4 Hz, 2H),2.72-2.83 (m, 4H), 2.91-3.04 (m, 5H), 3.38 (d, J=10.4, 2H), 3.75-3.88(m, 2H), 6.71 (dd, J=8.4, 2.8 Hz, 1H), 6.82 (d, J=2.8 Hz, 1H), 7.06 (d,J=8.4 Hz, 1H).

The 1H of NH could not be identified.

61ccis-4-[4-(4-Cyclobutylmethylpiperazin-1-yl)-3-(4,4-dimethylcyclohexyl)phenyl]-2,6-dimethylmorpholinehydrochloride

A mixture of thecis-4-[3-(4,4-dimethylcyclohexyl)-4-piperazin-1-ylphenyl]-2,6-dimethylmorpholine(30 mg, 0.0778 mmol) produced in Example (61b), bromomethylcyclobutane(23 mg, 0.156 mmol), potassium carbonate (22 mg, 0.156 mmol) anddimethylformamide (1 mL) was stirred for 1 hour at an externaltemperature of 80° C. Then, bromomethylcyclobutane (23 mg, 0.156 mmol)was further added and stirring was continued for 2 hours under the sameconditions. Saturated aqueous solution of sodium hydrogencarbonate wasadded to the reaction mixture and extraction was performed with ethylacetate. The separated organic layer was washed with water and brine inthat order, and then the solvent was distilled off by nitrogen stream.The resultant residue was purified by NH silica gel columnchromatography (ethyl acetate/hexane) to givecis-4-[4-(4-cyclobutylmethylpiperazin-1-yl)-3-(4,4-dimethylcyclohexyl)phenyl]-2,6-dimethylmorpholineas a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.98 (s, 3H), 1.02 (s, 3H), 1.15-2.15 (m,20H), 2.39 (dd, J=11.6, 10.4 Hz, 2H), 2.43-3.03 (m, 12H), 3.37 (d,J=10.4, 2H), 3.75-3.88 (m, 2H), 6.70 (dd, J=8.8, 2.8 Hz, 1H), 6.81 (d,J=2.8 Hz, 1H), 7.07 (d, J=8.8 Hz, 1H).

This compound was dissolved in ethyl acetate, and a 4N solution ofhydrogen chloride in ethyl acetate was added. The mixture wasconcentrated under reduced pressure. Hexane was added to the residue toproduce a solid, which was then triturated by sonication. Thesupernatant hexane solution was removed and the resulting solid wasdried to give 38 mg of the title compound as a colorless solid.

MS m/e (ESI) 454 (MH⁺).

Example 62 4-[2-(4-t-Butylcyclohexyl)phenyl]piperazine-1-carboxylic acidethyl ester

A mixture of the 1-[2-(4-t-butylcyclohexyl)phenyl]piperazine (92 mg,0.306 mmol) produced in Example (10a), triethylamine (0.085 mL, 0.612mmol) and dichloromethane (2 mL) was cooled in an ice bath and stirred.Ethyl chloroformate (0.032 mL, 0.337 mmol) was added to the mixture,followed by stirring for 2 hours under the same conditions. Saturatedaqueous solution of sodium hydrogencarbonate was added to the reactionmixture and extraction was performed with ethyl acetate. The separatedorganic layer was washed with water and brine in that order and thendried over anhydrous sodium sulfate. The desiccant was filtered off andthe filtrate was concentrated under reduced pressure. The resultantresidue was purified by NH silica gel column chromatography (ethylacetate/hexane) to give 100 mg of the title compound as a colorless oil,as a mixture of diastereomers at the position of t-butylcyclohexyl.

¹H-NMR (400 MHz, CDCl₃) δ: 0.88 (s, 9H×0.6), 0.90 (s, 9H×0.4), 1.10-2.00(m, 12H), 2.72-2.93 (m, 4H), 2.97-3.08 (m, 1H×0.4), 3.39-3.75 (m,4H+1H×0.6), 4.17 (q, J=7.2 Hz, 2H), 7.05-7.25 (m, 3H+1H×0.4), 7.45 (dd,J=8.0, 1.6 Hz, 1H×0.6). MS m/e (ESI) 373 (MH⁺).

Example 634-[4-[2-(4-t-Butylcyclohexyl)phenyl]piperazin-1-yl]butan-2-one

A mixture of the 1-[2-(4-t-butylcyclohexyl)phenyl]piperazine (30 mg,0.0998 mmol) produced in Example (10a) and chloroform (0.5 mL) wascooled in an ice bath and stirred. Methyl vinyl ketone (0.017 mL, 0.200mmol) was added to the mixture, followed by stirring for 2 hours underthe same conditions. The reaction mixture was purified by NH silica gelcolumn chromatography (ethyl acetate/hexane) to give 30 mg of the titlecompound as a colorless oil, as a mixture of diastereomers at theposition of t-butylcyclohexyl.

¹H-NMR (400 MHz, CDCl₃) δ: 0.88 (s, 9H×0.6), 0.90 (s, 9H×0.4), 1.10-1.99(m, 9H), 2.20 (s, 3H), 2.40-3.10 (m, 12H+1H×0.4), 3.34-3.43 (m, 1H×0.6),7.03-7.23 (m, 3H+1H×0.4), 7.42 (d, J=7.6 Hz, 1H×0.6).

Example 64 4-[4-[2-(4-t-Butylcyclohexyl)phenyl]piperazin-1-yl]butan-2-olhydrochloride

To a mixture of sodium borohydride (3 mg, 0.0675 mmol) and methanol (0.5mL) was added a mixture of the4-[4-[2-(4-t-butylcyclohexyl)phenyl]piperazin-1-yl]butan-2-one (25 mg,0.0675 mmol) produced in (Example 63) in methanol (0.5 mL), followed bystirring for 4 hours at room temperature.

Saturated aqueous solution of sodium hydrogencarbonate was added to thereaction mixture and extraction was performed with ethyl acetate. Theseparated organic layer was washed with water and brine in that orderand then dried over anhydrous sodium sulfate. The desiccant was filteredoff and the filtrate was concentrated under reduced pressure. Theresultant residue was purified by NH silica gel column chromatography(ethyl acetate/hexane) to give 23 mg of the title compound as acolorless oil, as a mixture of diastereomers at the positions oft-butylcyclohexyl and hydroxyl. This compound was dissolved in ethylacetate, and a 4N solution of hydrogen chloride in ethyl acetate wasadded. The precipitated solid was filtered to give 22 mg of the titlecompound as colorless crystals, as a mixture of diastereomers at thepositions of t-butylcyclohexyl and hydroxyl.

MS m/e (ESI) 373 (MH⁺).

Example 65 3-[4-[2-(4-t-Butylcyclohexyl)phenyl]piperazin-1-yl]propionicacid methyl ester

To a mixture of 1-[2-(4-t-butylcyclohexyl)phenyl]piperazine (530 mg,1.76 mmol) produced in Example (10a) and tetrahydrofuran (2 mL) wasadded methyl acrylate (0.24 mL, 2.65 mmol), followed by stirring for 12hours at an external temperature of 45° C. The reaction mixture wasconcentrated under reduced pressure and the resultant residue waspurified by NH silica gel column chromatography (ethyl acetate/hexane)to give 643 mg of the title compound as colorless crystals, as a mixtureof diastereomers at the position of t-butylcyclohexyl.

¹H-NMR (400 MHz, CDCl₃) δ: 0.88 (s, 9H×0.6), 0.90 (s, 9H×0.4), 1.08-1.99(m, 9H), 2.25-3.05 (m, 12H+1H×0.4), 3.35-3.42 (m, 1H×0.6), 3.70 (s, 3H),7.03-7.23 (m, 3H+1H×0.4), 7.42 (d, J=7.6 Hz, 1H×0.6). MS m/e (ESI) 387(MH⁺).

Example 66 3-[4-[2-(4-t-Butylcyclohexyl)phenyl]piperazin-1-yl]propionicacid

A mixture of3-[4-[2-(4-t-butyl-cyclohexyl)phenyl]piperazin-1-yl]propionic acidmethyl ester (600 mg, 1.55 mmol) produced in (Example 65), 2N aqueoussolution of sodium hydroxide (5 mL, 10 mmol), methanol (2 mL),tetrahydrofuran (2 mL) and water (1 mL) was stirred for 12 hours and 40minutes at room temperature. Then, 5N hydrochloric acid was added to thereaction mixture to adjust pH of the mixture to 6-7. The mixture wasconcentrated under reduced pressure. Methanol was then added thereto,the insoluble matters were filtered off, and the filtrate wasconcentrated under reduced pressure. The resultant residue was purifiedby NAM silica gel column chromatography (methanol/chloroform) to give abrown oil. Hexane was added thereto and the precipitated solid wasfiltered to give 414 mg of the title compound as colorless crystals, asa mixture of diastereomers at the position of t-butylcyclohexyl.

¹H-NMR (400 MHz, CDCl₃) δ: 0.89 (s, 9H×0.6), 0.90 (s, 9H×0.4), 1.06-1.99(m, 9H), 2.50-3.30 (m, 12H+1H×0.4), 3.32-3.39 (m, 1H×0.6), 7.07-7.24 (m,3H+1H×0.4), 7.44 (dd, J=8.0, 2.0 Hz, 1H×0.6).

The 1H of carboxylic acid could not be identified.

MS m/e (ESI) 373 (MH⁺).

Example 673-[4-[2-(4-t-Butylcyclohexyl)phenyl]piperazin-1-yl]-N-ethylpropionamidehydrochloride

A mixture of3-[4-[2-(4-t-butylcyclohexyl)phenyl]piperazin-1-yl]propionic acid (50mg, 0.134 mmol) produced in (Example 66),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (77 mg,0.403 mmol), 1-hydroxybenzotriazole monohydrate (62 mg, 0.403 mmol),ethylamine hydrochloride (55 mg, 0.671 mmol), triethylamine (0.09 mL,0.671 mmol) and dimethylformamide (1 mL) was stirred for 24 hours atroom temperature. Saturated aqueous solution of sodium hydrogencarbonatewas added to the reaction mixture and extraction was performed withethyl acetate. The separated organic layer was washed with water andbrine in that order and then dried over anhydrous sodium sulfate. Thedesiccant was filtered off and the filtrate was concentrated underreduced pressure. The resultant residue was purified by NH silica gelcolumn chromatography (ethyl acetate/hexane) to give 53 mg of3-[4-[2-(4-t-butylcyclohexyl)phenyl]piperazin-1-yl]-N-ethylpropionamideas a colorless oil, as a mixture of diastereomers at the position oft-butylcyclohexyl.

¹H-NMR (400 MHz, CDCl₃) δ: 0.89 (s, 9H×0.6), 0.90 (s, 9H×0.4), 1.08-1.99(m, 12H), 2.35-3.04 (m, 12H+1H×0.4), 3.24-3.42 (m, 2H+1H×0.6), 7.07-7.25(m, 3H+1H×0.4), 7.44 (dd, J=7.6, 1.6 Hz, 1H×0.6).

The 1H of NH could not be identified.

MS m/e (ESI) 400 (MH⁺).

This compound was dissolved in ethyl acetate, and a 4N solution ofhydrogen chloride in ethyl acetate was added. The precipitated solid wasfiltered to give 49 mg of the title compound as colorless crystals, as amixture of diastereomers at the position of t-butylcyclohexyl.

Example 681-[2-(4,4-Dimethylcyclohexyl)phenyl]-4-furan-2-ylmethylpiperazinehydrochloride

To a mixture of 1-[2-(4,4-dimethylcyclohexyl)phenyl]piperazine (30 mg,0.11 mmol) produced in Example (3c), furan-2-carbaldehyde (21 mg, 0.22mmol) and tetrahydrofuran (2 mL) was added sodium triacetoxyborohydride(119 mg, 0.559 mmol), followed by stirring for 1 hour and 50 minutes atroom temperature. Saturated aqueous solution of sodium hydrogencarbonatewas added to the reaction mixture and extraction was performed withethyl acetate. The separated organic layer was filtered through Celite.The solvent was distilled off by nitrogen stream to the filtrate. Theresultant residue was purified by NH silica gel column chromatography(ethyl acetate/heptane) to give1-[2-(4,4-dimethylcyclohexyl)phenyl]-4-furan-2-ylmethylpiperazine. Thiscompound was dissolved in dichloromethane, and a 4N solution of hydrogenchloride in ethyl acetate was added. The solvent was distilled off bynitrogen stream. Hexane was added to the obtained residue to produce asolid, which was then triturated by sonication. The supernatant hexanesolution was removed and the resulting solid was dried to give 38 mg ofthe title compound as colorless crystals.

MS m/e (ESI) 353 (MH⁺).

Example 691-[2-(4,4-Dimethylcyclohexyl)phenyl]-4-furan-3-ylmethylpiperazinehydrochloride

To a mixture of 1-[2-(4,4-dimethylcyclohexyl)phenyl]piperazine (30 mg,0.11 mmol) produced in Example (3c), furan-3-carbaldehyde (21 mg, 0.22mmol) and tetrahydrofuran (2 mL) was added sodium triacetoxyborohydride(119 mg, 0.559 mmol), followed by stirring for 1 hour and 50 minutes atroom temperature. Saturated aqueous solution of sodium hydrogencarbonatewas added to the reaction mixture and extraction was performed withethyl acetate. The separated organic layer was filtered through Celite.The solvent was distilled off by nitrogen stream to the filtrate. Theresultant residue was purified by NH silica gel column chromatography(ethyl acetate/heptane) to give1-[2-(4,4-dimethylcyclohexyl)phenyl]-4-furan-3-ylmethylpiperazine. Thiscompound was dissolved in dichloromethane, and a 4N solution of hydrogenchloride in ethyl acetate was added. The solvent was distilled off bynitrogen stream. Hexane was added to the obtained residue to produce asolid, which was then triturated by sonication. The supernatant hexanesolution was removed and the resulting solid was dried to give 31 mg ofthe title compound as colorless crystals.

MS m/e (ESI) 353 (MH⁺).

Example 701-[4-Methyl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-propylpiperazinehydrochloride

70a4-[4-Methyl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine-1-carboxylicacid t-butyl ester

A mixture of4-[4-bromo-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine-1-carboxylicacid t-butyl ester (200 mg, 0.417 mmol) produced in Example (99a),cesium carbonate (408 mg, 1.25 mmol),tetrakis(triphenylphosphine)palladium(0) (50 mg, 0.0417 mmol) anddimethylformamide (4 mL) was stirred at room temperature under anitrogen atmosphere. Trimethylboroxine (0.06 mL, 0.417 mmol) was addedto the mixture, and stirring was continued for 9 hours at an externaltemperature of 100° C. Ethyl acetate and water were added to thereaction mixture and extraction was performed with ethyl acetate. Theseparated organic layer was washed with water and brine in that orderand then dried over anhydrous magnesium sulfate. The desiccant wasfiltered off and the filtrate was concentrated under reduced pressure.The resultant residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give 124 mg of the title compound as colorlesscrystals.

¹H-NMR (400 MHz, CDCl₃) δ: 0.93 (s, 6H), 1.11 (s, 6H), 1.13-1.44 (m,6H), 1.48 (s, 9H), 2.30 (s, 3H), 2.79 (brs, 4H), 3.57 (tt, J=12.4, 2.8Hz, 1H), 6.94-6.97 (m, 2H), 7.03 (brs, 1H).

The 4H of piperazine ring could not be identified.

70b 1-[4-Methyl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine

A mixture of4-[4-methyl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine-1-carboxylicacid t-butyl ester (124 mg, 0.299 mmol) produced in Example (70a),trifluoroacetic acid (1 mL, 12.9 mmol) and dichloromethane (2 mL) wasstirred for 2 hours and 30 minutes at room temperature. Saturatedaqueous solution of sodium hydrogencarbonate was added to the reactionmixture and extraction was performed with ethyl acetate. The separatedorganic layer was concentrated under reduced pressure. The resultantresidue was purified by NH silica gel column chromatography (ethylacetate/hexane) to give 85 mg of the title compound as yellow crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 0.93 (s, 6H), 1.12 (s, 6H), 1.13-1.48 (m,6H), 2.30 (s, 3H), 2.82 (t, J=4.8 Hz, 4H), 3.02 (t, J=4.8 Hz, 4H), 3.59(tt, J=12.4, 2.8 Hz, 1H), 6.97 (ddd, J=8.4, 2.0, 0.8 Hz, 1H), 6.99-7.05(m, 2H).

The 1H of NH could not be identified.

70c1-[4-Methyl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-propylpiperazinehydrochloride

To a mixture of1-[4-methyl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (55 mg,0.175 mmol) produced in Example (70b), propionaldehyde (20 mg, 0.350mmol) and tetrahydrofuran (2 mL) was added sodium triacetoxyborohydride(75 mg, 0.350 mmol), followed by stirring for 1 hour and 15 minutes atroom temperature. Saturated aqueous solution of sodium hydrogencarbonatewas added to the reaction mixture and extraction was performed withethyl acetate. The separated organic layer was dried over anhydroussodium sulfate. The desiccant was filtered off and the filtrate wasconcentrated under reduced pressure. The resultant residue was purifiedby NH silica gel column chromatography (ethyl acetate/heptane) to give56 mg of1-[4-methyl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-propylpiperazineas a colorless solid.

This compound was dissolved in dichloromethane, and then a 4N solutionof hydrogen chloride in ethyl acetate was added and the mixture wasconcentrated under reduced pressure. Diethyl ether-hexane was added tothe obtained residue to produce a solid, which was then triturated bysonication. The supernatant diethyl ether-hexane solution was removedand the resulting solid was dried to give 54 mg of the title compound asa colorless solid.

¹H-NMR (400 MHz, CDCl₃) δ: 0.91-0.95 (m, 9H), 1.12 (s, 6H), 1.13-1.60(m, 8H), 2.29 (s, 3H), 2.34-2.38 (m, 2H), 2.59 (brs, 4H), 2.88-2.2.90(m, 4H), 3.56 (tt, J=12.4, 2.8 Hz, 1H), 6.93-6.95 (m, 1H), 7.01-7.03 (m,2H). MS m/e (ESI) 357 (MH⁺).

Example 711-[3-Methyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]-4-propylpiperazinehydrochloride

71a 1-Methyl-3-nitro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)benzene

A mixture of4,4,5,5-tetramethyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)[1,3,2]dioxaborolane(3.96 g, 15 mmol) produced in Example (4b), 2-bromo-3-nitrotoluene (2.48g, 11.5 mmol), tetrakis(triphenylphosphine)palladium(0) (1.33 g, 1.15mmol), tripotassium phosphate (3.66 g, 17.3 mmol), 1,2-dimethoxyethane(30 mL) and water (10 mL) was stirred for 10 hours and 20 minutes at anexternal temperature of 80° C. under a nitrogen atmosphere. Ethylacetate and water were added to the reaction mixture, and it wasfiltered through Celite. The filtrate was then extracted with ethylacetate. The separated organic layer was washed with water and brine inthat order and then dried over anhydrous magnesium sulfate. Thedesiccant was filtered off and the filtrate was concentrated underreduced pressure. The resultant residue was purified by NH silica gelcolumn chromatography (hexane) to give 3.14 g of the title compound as ayellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.01 (s, 3H), 1.06 (s, 3H), 1.07 (s, 3H),1.10 (s, 3H), 1.37-1.46 (m, 2H), 1.90 (d, J=17.2 Hz, 1H), 2.14 (dd,J=17.2, 2.0 Hz, 1H), 2.33 (s, 3H), 5.23 (t, J=2.0 Hz, 1H), 7.24 (dd,J=8.0, 7.6 Hz, 1H), 7.36 (d, J=7.6 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H).

71b 3-Methyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenylamine

A mixture of the1-methyl-3-nitro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)benzene (1 g,3.66 mmol) produced in Example (71a), iron powder (631 mg, 11.0 mmol),ammonium chloride (783 mg, 14.6 mmol), ethanol (15 mL), water (6 mL) anddimethylformamide (1 mL) was stirred for 3 hours and 30 minutes at anexternal temperature of 90° C. under a nitrogen atmosphere. Ethylacetate and water were added to the reaction mixture, and it wasfiltered through Celite. The filtrate was then extracted with ethylacetate. The separated organic layer was washed with water and brine inthat order and then dried over anhydrous sodium sulfate. The desiccantwas filtered off and the filtrate was concentrated under reducedpressure. The resultant residue was purified by NH silica gel columnchromatography (ethyl acetate/hexane) to give 663 mg of the titlecompound as a light yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.074 (s, 3H), 1.076 (s, 3H), 1.098 (s, 3H),1.101 (s, 3H), 1.45 (s, 2H), 1.85 (dd, J=17.2, 1.2 Hz, 1H), 1.95 (dd,J=17.2, 1.2 Hz, 1H), 2.18 (s, 3H), 3.65 (brs, 2H), 5.38 (brs, 1H), 6.55(d, J=7.6 Hz, 1H), 6.61 (d, J=7.2 Hz, 1H), 6.94 (dd, J=7.6, 7.2 Hz,11H).

71c 1-[3-Methyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazine

To a mixture of3-methyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenylamine (663 mg, 2.72mmol) produced in Example (71b) and 1,2-dichlorobenzene (3 mL) was addedbis(2-chloroethyl)amine hydrochloride (632 mg, 3.54 mmol), followed bystirring for 5 hours and 50 minutes at an external temperature of 200°C. under a nitrogen atmosphere. During the reaction, a nitrogen streamwas passed through the reactor several times. The reaction mixture wascooled to room temperature, chloroform and saturated solution of sodiumhydrogencarbonate were added, and the filtrate obtained by filtrationthrough Celite was extracted with chloroform. The separated organiclayer was washed with brine and then dried over anhydrous sodiumsulfate. The desiccant was filtered off and the filtrate wasconcentrated under reduced pressure. The resultant residue was purifiedby NH silica gel column chromatography (ethyl acetate/hexane) to give625 mg of the title compound as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 1.05 (s, 6H), 1.11 (s, 6H), 1.43 (s, 2H),1.65 (d, J=16.8 Hz, 1H), 2.23 (s, 3H), 2.38 (d, J=16.8 Hz, 1H),2.59-2.70 (m, 2H), 2.84-2.93 (m, 2H), 2.95-3.03 (m, 2H), 3.08-3.16 (m,2H), 5.17 (s, 1H), 6.94 (d, J=7.2 Hz, 1H), 6.96 (d, J=8.0 Hz, 1H), 7.11(dd, J=8.0, 7.2 Hz, 1H).

The 1H of NH could not be identified.

71d1-[3-Methyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]-4-propylpiperazinehydrochloride

To a mixture of1-[3-methyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazine (115mg, 0.368 mmol) produced in Example (71c), propionaldehyde (0.079 mL,1.1 mmol) and tetrahydrofuran (2 mL) was added sodiumtriacetoxyborohydride (246 mg, 1.1 mmol), followed by stirring for 1hour and 30 minutes at room temperature. Saturated aqueous solution ofsodium hydrogencarbonate was added to the reaction mixture andextraction was performed with ethyl acetate. The separated organic layerwas washed with water and brine in that order and then dried overanhydrous sodium sulfate. The desiccant was filtered off and thefiltrate was concentrated under reduced pressure. The resultant residuewas purified by NH silica gel column chromatography (ethylacetate/hexane) to give 124 mg of1-[3-methyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]-4-propylpiperazineas colorless crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 0.92 (t, J=7.6 Hz, 3H), 1.05 (s, 6H), 1.10(s, 3H), 1.11 (s, 3H), 1.43 (s, 2H), 1.48-1.57 (m, 2H), 1.64 (d, J=17.2Hz, 1H), 2.23 (s, 3H), 2.31-2.35 (m, 2H), 2.38 (d, J=17.2 Hz, 1H),2.42-2.66 (m, 4H), 2.67-2.78 (m, 2H), 3.18-3.28 (m, 2H), 5.18 (s, 1H),6.94 (d, J=7.2 Hz, 1H), 6.99 (d, J=7.6 Hz, 1H), 7.11 (dd, J=7.6, 7.2 Hz,1H).

This compound was dissolved in dichloromethane, and then a 4N solutionof hydrogen chloride in ethyl acetate was added and the mixture wasconcentrated under reduced pressure. Diethyl ether-hexane was added tothe obtained residue to produce a solid, which was triturated bysonication. It was then was filtered and dried to give 134 mg of thetitle compound as a colorless solid.

MS m/e (ESI) 355 (MH⁺).

Example 721-[5-Methoxy-4-piperidin-1-yl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-propylpiperazinehydrochloride

72a4-[5-Methoxy-4-piperidin-1-yl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine-1-carboxylicacid t-butyl ester

A mixture of4-[4-bromo-5-methoxy-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine-1-carboxylicacid t-butyl ester (509 mg, 1 mmol) produced by a synthetic proceduresimilar to Example (43c), piperidine (128 mg, 1.5 mmol), sodiumt-butoxide (240 mg, 2.5 mmol), palladium(II) acetate (22 mg, 0.1 mmol),tri-t-butylphosphonium tetrafluoroborate (87 mg, 0.3 mmol) and xylene (3mL) was stirred for 20 hours at an external temperature of 100° C. undera nitrogen atmosphere, and was then further stirred for 12 hours at anexternal temperature of 120° C. Ethyl acetate and water were added tothe reaction mixture, which was then passed through Celite to removeinsoluble materials. The resultant filtrate was extracted with ethylacetate. The separated organic layer was washed with water and brine andthen dried over anhydrous sodium sulfate. The desiccant was filtered offand the filtrate was concentrated under reduced pressure. The resultantresidue was purified by silica gel column chromatography (ethylacetate/hexane) to give 88 mg of the title compound as red crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 0.92 (s, 6H), 1.10 (s, 6H), 1.14-1.65 (m,17H), 1.74 (brs, 4H), 2.80 (brs, 4H), 2.95 (brs, 4H), 3.54 (t, J=12.4Hz, 1H), 3.81 (s, 3H), 6.59 (s, 1H), 6.77 (s, 1H).

4H could not be identified.

72b1-[5-Methoxy-4-piperidin-1-yl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine

A mixture of the4-[5-methoxy-4-piperidin-1-yl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine-1-carboxylicacid t-butyl ester (88 mg, 0.17 mmol) produced in Example (72a),trifluoroacetic acid (0.25 mL, 3.2 mmol) and dichloromethane (0.5 mL)was stirred for 1 hour and 10 minutes at room temperature. Saturatedaqueous solution of sodium hydrogencarbonate was added to the reactionmixture and extraction was performed with ethyl acetate. The separatedorganic layer was dried over anhydrous sodium sulfate. The desiccant wasfiltered off and the filtrate was concentrated under reduced pressure.The resultant residue was purified by NH silica gel columnchromatography (ethyl acetate/heptane) to give 56 mg of the titlecompound as a red solid.

¹H-NMR (400 MHz, CDCl₃) δ: 0.93 (s, 6H), 1.12 (s, 6H), 1.14-1.65 (m,8H), 1.71-1.77 (m, 4H), 2.81-2.83 (m, 4H), 2.95 (t, J=5.2 Hz, 4H),2.99-3.02 (m, 4H), 3.56 (tt, J=12.4, 2.8 Hz, 1H), 3.83 (s, 3H), 6.66 (s,1H), 6.77 (s, 1H).

The 1H of NH could not be identified.

72c1-[5-Methoxy-4-piperidin-1-yl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-propylpiperazinehydrochloride

To a mixture of1-[5-methoxy-4-piperidin-1-yl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine(5 mg, 0.0121 mmol) produced in Example (72b), propionaldehyde (1.4 mg,0.0242 mmol) and tetrahydrofuran (0.3 mL) was added sodiumtriacetoxyborohydride (5 mg, 0.0242 mmol), followed by stirring for 1hour and 10 minutes at room temperature. Saturated aqueous solution ofsodium hydrogencarbonate was added to the reaction mixture andextraction was performed with ethyl acetate. The solvent was distilledoff nitrogen stream to the separated organic layer. The resultantresidue was purified by NH silica gel column chromatography (ethylacetate/hexane) to give1-[5-methoxy-4-piperidin-1-yl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-propylpiperazine.This compound was dissolved in dichloromethane, and a 4N solution ofhydrogen chloride in ethyl acetate was added. The solvent was distilledof by nitrogen stream. Heptane was added to the obtained residue toproduce a solid, which was then triturated by sonication. Thesupernatant heptane solution was removed and the resulting solid wasdried to give 6.1 mg of the title compound as a colorless solid.

¹H-NMR (400 MHz, CDCl₃) δ: 0.94 (s, 6H), 1.055 (t, J=7.6 Hz, 3H), 1.06(s, 6H), 1.18-2.08 (m, 12H), 2.66-2.80 (m, 2H), 2.87-3.08 (m, 4H),3.21-3.31 (m, 2H), 3.44-3.91 (m, 9H), 3.94 (s, 3H), 6.80 (s, 1H), 8.56(s, 1H). MS m/e (ESI) 456 (MH⁺).

Example 731-(2-Fluoroethyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

A mixture of 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (30mg, 0.1 mmol) produced in Example (8b), 1-bromo-2-fluoroethane (16.2 mg,0.125 mmol), sodium iodide (1.5 mg, 0.01 mmol), potassium carbonate(20.8 mg, 0.15 mmol) and dimethylformamide (1 mL) was stirred for 2hours at an external temperature of 80° C. Saturated aqueous solution ofsodium hydrogencarbonate was added to the reaction mixture andextraction was performed with diethyl ether. The solvent was distilledoff by nitrogen stream to the separated organic layer. The resultantresidue was purified by NH silica gel column chromatography (ethylacetate/heptane) to give1-(2-fluoroethyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine.

¹H-NMR (400 MHz, CDCl₃) δ: 0.93 (s, 6H), 1.13 (s, 6H), 1.15 (d, J=13.6Hz, 1H), 1.23 (dd, J=12.4, 12.4 Hz, 2H), 1.33 (dt, J=13.6, 2.0 Hz, 1H),1.40-1.48 (m, 2H), 2.71 (brs, 4H), 2.77 (dt, J=28.4, 4.8 Hz, 2H), 2.95(t, J=4.8 Hz, 4H), 3.57 (tt, J=12.4, 2.8 Hz, 1H), 4.57 (dt, J=47.6, 4.8Hz, 2H), 7.05-7.18 (m, 3H), 7.23 (dd, J=7.6, 1.6 Hz, 1H).

This compound was dissolved in dichloromethane, and a 4N solution ofhydrogen chloride in ethyl acetate was added. The solvent was distilledoff by nitrogen stream. Diethyl ether-heptane was added to the resultantresidue to produce a solid, which was then triturated by sonication. Thesupernatant diethyl ether-heptane solution was removed and the resultingsolid was dried to give 27.5 mg of the title compound as a colorlesssolid.

MS m/e (ESI) 347 (MH⁺).

Example 741-(2,2-Difluoroethyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

A mixture of 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (30mg, 0.1 mmol) produced in Example (8b), 2-bromo-1,1-difluoroethane (18.1mg, 0.125 mmol), sodium iodide (1.5 mg, 0.01 mmol), potassium carbonate(20.8 mg, 0.15 mmol) and dimethylformamide (1 mL) was stirred for 2hours at an external temperature of 80° C. After then further adding2-bromo-1,1-difluoroethane (18.1 mg, 0.125 mmol) to the reactionmixture, it was further stirred for 6 hours and 30 minutes at anexternal temperature of 80° C. Saturated aqueous solution of sodiumhydrogencarbonate was added to the reaction mixture and extraction wasperformed with diethyl ether. The solvent was distilled off by nitrogenstream to the separated organic layer. The resultant residue waspurified by NH silica gel column chromatography (ethyl acetate/heptane)to give1-(2,2-difluoroethyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine.

¹H-NMR (400 MHz, CDCl₃) δ: 0.93 (s, 6H), 1.12 (s, 6H), 1.17 (d, J=14.0Hz, 1H), 1.23 (dd, J=12.8, 12.8 Hz, 2H), 1.33 (dt, J=13.6, 2.0 Hz, 1H),1.38-1.46 (m, 2H), 2.75 (brs, 4H), 2.81 (td, J=14.8, 4.4 Hz, 2H), 2.93(t, J=4.8 Hz, 4H), 3.55 (tt, J=12.8, 2.8 Hz, 1H), 5.93 (tt, J=56.0, 4.4Hz, 1H), 7.05-7.18 (m, 3H), 7.23 (dd, J=7.6, 1.6 Hz, 1H).

This compound was dissolved in dichloromethane, and a 4N solution ofhydrogen chloride in ethyl acetate was added. The solvent was distilledoff by nitrogen stream. Diethyl ether-heptane was added to the obtainedresidue to produce a solid, which was then triturated by sonication. Thesupernatant diethyl ether-heptane solution was removed and the resultingsolid was dried to give 15.3 mg of the title compound as a colorlesssolid.

MS m/e (ESI) 365 (MH⁺).

Example 751-(3-Fluoropropyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

A mixture of 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (30mg, 0.1 mmol) produced in Example (8b), 1-bromo-3-fluoropropane (18.0mg, 0.125 mmol), sodium iodide (1.5 mg, 0.01 mmol), potassium carbonate(20.8 mg, 0.15 mmol) and dimethylformamide (1 mL) was stirred for 2hours at an external temperature of 80° C. Saturated aqueous solution ofsodium hydrogencarbonate was added to the reaction mixture andextraction was performed with diethyl ether. The solvent was distilledoff by nitrogen stream to the separated organic layer. The resultantresidue was purified by NH silica gel column chromatography (ethylacetate/beptane) to give1-(3-fluoropropyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine.

¹H-NMR (400 MHz, CDCl₃) δ: 0.93 (s, 6H), 1.12 (s, 6H), 1.15 (d, J=14.0Hz, 1H), 1.23 (dd, J=12.8, 12.8 Hz, 2H), 1.33 (dt, J=13.6, 2.0 Hz, 1H),1.38-1.47 (m, 2H), 1.86-2.01 (m, 2H), 2.53-2.57 (m, 2H), 2.61 (brs, 4H),2.92 (t, J=4.8 Hz, 4H), 3.57 (tt, J=12.8, 2.8 Hz, 1H), 4.56 (dt, J=47.2,6.0 Hz, 2H), 7.04-7.18 (m, 3H), 7.25 (dd, J=7.2, 2.0 Hz, 1H).

This compound was dissolved in dichloromethane, and a 4N solution ofhydrogen chloride in ethyl acetate was added. The solvent was distilledoff by nitrogen stream. Diethyl ether-heptane was added to the obtainedresidue to produce a solid, which was then triturated by sonication. Thesupernatant diethyl ether-heptane solution was removed and the resultingsolid was dried to give 27.8 mg of the title compound as a colorlesssolid.

MS m/e (ESI) 361 (MH⁺).

Example 761-(4-Fluorobutyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

A mixture of 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (30mg, 0.1 mmol) produced in Example (8b), 1-bromo-4-fluorobutane (19.8 mg,0.125 mmol), sodium iodide (1.5 mg, 0.01 mmol), potassium carbonate(20.8 mg, 0.15 mmol) and dimethylformamide (1 mL) was stirred for 2hours at an external temperature of 80° C. Saturated aqueous solution ofsodium hydrogencarbonate was added to the reaction mixture andextraction was performed with diethyl ether. The solvent was distilledoff by nitrogen stream to the separated organic layer. The resultantresidue was purified by NH silica gel column chromatography (ethylacetate/heptane) to give1-(4-fluorobutyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine.

¹H-NMR (400 MHz, CDCl₃) δ: 0.93 (s, 6H), 1.12 (s, 6H), 1.15 (d, J=14.0Hz, 1H), 1.23 (dd, J=12.4, 12.4 Hz, 2H), 1.32 (dt, J=13.6, 2.0 Hz, 1H),1.39-1.48 (m, 2H), 1.60-1.84 (m, 4H), 2.43-2.46 (m, 2H), 2.61 (brs, 4H),2.92 (t, J=4.8 Hz, 4H), 3.57 (tt, J=12.8, 2.8 Hz, 1H), 4.49 (dt, J=47.2,6.0 Hz, 2H), 7.04-7.18 (m, 3H), 7.22 (dd, J=7.6, 1.6 Hz, 1H).

This compound was dissolved in dichloromethane, and a 4N solution ofhydrogen chloride in ethyl acetate was added. The solvent was distilledoff by nitrogen stream. Diethyl ether-heptane was added to the obtainedresidue to produce a solid, which was then triturated by sonication. Thesupernatant diethyl ether-heptane solution was removed and the resultingsolid was dried to give 27.3 mg of the title compound as a colorlesssolid.

MS m/e (ESI) 375 (MH⁺).

Example 77 1-Allyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

A mixture of 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (30mg, 0.1 mmol) produced in Example (8b), allyl bromide (14.8 mg, 0.12mmol), potassium carbonate (20.8 mg, 0.15 mmol) and dimethylformamide (1mL) was stirred for 4 hours and 20 minutes at an external temperature of80° C. Saturated aqueous solution of sodium hydrogencarbonate was addedto the reaction mixture and extraction was performed with ethylacetate-dichloromethane. The separated organic layer was washed withwater, and then the solvent was distilled off by nitrogen stream. Theresultant residue was purified by NH silica gel column chromatography(ethyl acetate/heptane) to give1-allyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine.

¹H-NMR (400 MHz, CDCl₃) δ: 0.93 (s, 6H), 1.13 (s, 6H), 1.15-1.28 (m,3H), 1.33 (dt, J=13.6, 2.0 Hz, 1H), 1.38-1.48 (m, 2H), 2.60 (brs, 4H),2.93 (t, J=4.8 Hz, 4H), 3.07 (ddd, J=6.8, 1.2, 1.2 Hz, 2H), 3.57 (tt,J=12.4, 2.8 Hz, 1H), 5.16-5.19 (m, 1H), 5.21-5.26 (m, 1H), 5.20 (ddt,J=17.2, 10.0, 6.8 Hz, 1H), 7.04-7.18 (m, 3H), 7.20-7.25 (m, 1H).

This compound was dissolved in dichloromethane, and a 4N solution ofhydrogen chloride in ethyl acetate was added. The solvent was distilledoff by nitrogen stream. Diethyl ether-heptane was added to the obtainedresidue to produce a solid, which was then triturated by sonication. Thesupernatant diethyl ether-heptane solution was removed and the resultingsolid was dried to give 17.7 mg of the title compound as a colorlesssolid.

MS m/e (ESI) 341 (MH⁺).

Example 781-Prop-2-ynyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

A mixture of 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (30mg, 0.1 mmol) produced in Example (8b), propargyl bromide (14.3 mg, 0.12mmol), potassium carbonate (20.8 mg, 0.15 mmol) and dimethylformamide (1mL) was stirred for 4 hours and 20 minutes at an external temperature of80° C. Saturated aqueous solution of sodium hydrogencarbonate was addedto the reaction mixture and extraction was performed with ethylacetate-dichloromethane. The separated organic layer was washed withwater, and then the solvent was distilled off by nitrogen stream. Theresultant residue was purified by NH silica gel column chromatography(ethyl acetate/heptane) to give1-prop-2-ynyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine.

¹H-NMR (400 MHz, CDCl₃) δ: 0.93 (s, 6H), 1.13 (s, 6H), 1.14-1.36 (m,4H), 1.40-1.48 (m, 2H), 2.27 (t, J=2.4 Hz, 1H), 2.75 (brs, 4H), 2.96 (t,J=4.8 Hz, 4H), 3.37 (d, J=2.4 Hz, 2H), 3.56 (tt, J=12.4, 2.8 Hz, 1H),7.05-7.18 (m, 3H), 7.23 (dd, J=8.0, 1.6 Hz, 1H).

This compound was dissolved in dichloromethane, and a 4N solution ofhydrogen chloride in ethyl acetate was added. The solvent was distilledoff by nitrogen stream. Diethyl ether-heptane was added to the obtainedresidue to produce a solid, which was then triturated by sonication. Thesupernatant diethyl ether-heptane solution was removed and the resultingsolid was dried to give 6.6 mg of the title compound as a colorlesssolid.

MS m/e (ESI) 339 (MH⁺).

Example 791-But-2-ynyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

A mixture of the 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine(30 mg, 0.1 mmol) produced in Example (8b), 1-bromo-2-butyne (16.1 mg,0.12 mmol), potassium carbonate (20.8 mg, 0.15 mmol) anddimethylformamide (1 mL) was stirred for 4 hours and 20 minutes at anexternal temperature of 80° C. Saturated aqueous solution of sodiumhydrogencarbonate was added to the reaction mixture and extraction wasperformed with diethyl ether. The separated organic layer was washedwith water, and then the solvent was distilled off by nitrogen stream.The resultant residue was purified by NH silica gel columnchromatography (ethyl acetate/heptane) to give1-but-2-ynyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine.

¹H-NMR (400 MHz, CDCl₃) δ: 0.93 (s, 6H), 1.14 (s, 6H), 1.14-1.36 (m,4H), 1.40-1.48 (m, 2H), 1.84 (t, J=2.4 Hz, 3H), 2.73 (brs, 4H), 2.96 (t,J=4.8 Hz, 4H), 3.28 (q, J=2.4 Hz, 2H), 3.57 (tt, J=12.8, 2.8 Hz, 1H),7.05-7.18 (m, 3H), 7.22 (dd, J=7.6, 1.6 Hz, 1H).

This compound was dissolved in dichloromethane, and a 4N solution ofhydrogen chloride in ethyl acetate was added. The solvent was distilledoff by nitrogen stream. Diethyl ether-heptane was added to the obtainedresidue to produce a solid, which was then triturated by sonication. Thesupernatant diethyl ether-heptane solution was removed and the resultingsolid was dried to give 11.2 mg of the title compound as a colorlesssolid.

MS m/e (ESI) 353 (MH⁺).

Example 801-[2-(3,3,5,5-Tetramethylcyclohexyl)phenyl]-4-(4,4,4-trifluorobutyl)piperazinehydrochloride

A mixture of the 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine(30 mg, 0.1 mmol) produced in Example (8b),1-bromo-4,4,4-trifluorobutane (24.4 mg, 0.125 mmol), sodium iodide (1.5mg, 0.01 mmol), potassium carbonate (20.8 mg, 0.15 mmol) anddimethylformamide (1 mL) was stirred for 2 hours and 30 minutes at anexternal temperature of 60° C. Aqueous solution of sodiumhydrogencarbonate was added to the reaction mixture and extraction wasperformed with diethyl ether. The solvent was distilled off by nitrogenstream to the separated organic layer. The resultant residue waspurified by NH silica gel column chromatography (ethyl acetate/heptane)to give1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-(4,4,4-trifluorobutyl)piperazine.

This compound was dissolved in dichloromethane, and a 4N solution ofhydrogen chloride in ethyl acetate was added. The solvent was distilledoff by nitrogen stream. Diethyl ether-heptane was added to the obtainedresidue to produce a solid, which was then triturated by sonication. Thesupernatant diethyl ether-heptane solution was removed and the resultingsolid was dried to give 27.5 mg of the title compound as a colorlesssolid.

¹H-NMR (400 MHz, CD₃OD) δ: 0.95 (s, 6H), 1.17 (s, 6H), 1.19-1.42 (m,6H), 1.98-2.09 (m, 2H), 2.28-2.40 (m, 2H), 3.15 (s, 4H), 3.20-3.90 (m,7H), 7.12-7.20 (m, 3H), 7.26-7.30 (m, 1H). MS m/e (ESI) 411 (MH⁺).

Example 814-[3-(4-Butylpiperazin-1-yl)-4-(3,3,5,5-tetramethylcyclohexyl)phenyl]morpholinehydrochloride

81a 3-Piperazin-1-yl-4-(3,3,5,5-tetramethylcyclohexyl)phenol

1-[5-Methoxy-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazineproduced in Example (27c) was used as a starting material forN-butyloxycarbonylation and hydrogenation by conventional methods. Amixture of4-[5-methoxy-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine-1-carboxylicacid t-butyl ester (3.41 g, 7.92 mmol) obtained by the reaction, aceticacid (18 mL, 314 mmol) and 48% hydrobromic acid (36 mL, 318 mmol) wasstirred for 8 hours and 20 minutes at an external temperature of 130° C.The reaction mixture was cooled in an ice water bath and stirred, andthen 5N aqueous solution of sodium hydroxide was added dropwise theretoto adjust pH of the mixture to 8-9. The resultant solid was filtered togive 2.98 g of a crude product of the title compound as a light redsolid.

¹H-NMR (400 MHz, CD₃OD) δ: 0.94 (s, 6H), 1.54 (s, 6H), 1.17-1.40 (m,6H), 3.05 (t, J=4.8 Hz, 4H), 3.42 (tt, J=12.8, 2.8 Hz, 1H), 6.55-6.61(m, 2H), 7.05 (d, J=8.0 Hz, 1H).

The 4H of piperazine ring and the 2H of NH and OH could not beidentified.

81b4-[5-Hydroxy-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine-1-carboxylicacid t-butyl ester

A mixture of the crude product of3-piperazin-1-yl-4-(3,3,5,5-tetramethylcyclohexyl)phenol produced inExample (81a) (2.98 g) and a mixed solvent of chloroform-methanol (100mL) was stirred at an external temperature of 0° C. A solution ofdi-t-butyl dicarbonate (1.81 g, 8.32 mmol) in chloroform was addeddropwise thereto. After stirring for 2 hours and 30 minutes, thereaction mixture was concentrated under reduced pressure. Saturatedaqueous solution of sodium carbonate and ethyl acetate were added to theobtained residue and extraction was performed with ethyl acetate. Theseparated organic layer was washed with water and brine in that orderand then dried over anhydrous sodium sulfate. The desiccant was filteredoff and the filtrate was concentrated under reduced pressure. Theobtained residue was purified by NH silica gel column chromatography(ethyl acetate/heptane) to give 2.95 g of the title compound as a lightred solid.

¹H-NMR (400 MHz, CDCl₃) δ: 0.91 (s, 6H), 1.10 (s, 6H), 1.11-1.43 (m,6H), 1.49 (s, 9H), 2.80 (brs, 4H), 3.43 (tt, J=12.4, 2.8 Hz, 1H), 3.52(brs, 4H), 6.55-6.57 (m, 2H), 7.06 (dd, J=7.2, 1.6 Hz, 1H).

The 1H of OH could not be identified.

81c4-[5-(Nonafluorobutane-1-sulfonyloxy)-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine-1-carboxylicacid t-butyl ester

A mixture of4-[5-hydroxy-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine-1-carboxylicacid t-butyl ester (1.5 g, 3.60 mmol) produced in Example (81b),4-dimethylaminopyridine (22.2 mg, 0.18 mmol), diisopropylethylamine(0.758 mL, 4.32 mmol) and dichloromethane (10 mL) was cooled in an icewater bath and stirred under a nitrogen atmosphere.

Perfluorobutanesulfonyl fluoride (0.773 mL, 3.96 mmol) was then addeddropwise thereto. After stirring for 1 hour and 20 minutes under thesame conditions, stirring was continued for 16 hours at roomtemperature. Water was added to the reaction mixture and extraction wasperformed with dichloromethane. The separated organic layer was washedwith brine and then dried over anhydrous magnesium sulfate. Thedesiccant was filtered off and the filtrate was concentrated underreduced pressure. The resultant residue was purified by NH silica gelcolumn chromatography (ethyl acetate/heptane) to give 2.41 g of thetitle compound as a light yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.93 (s, 6H), 1.11 (s, 6H), 1.13-1.46 (m,6H), 1.49 (s, 9H), 2.82 (brs, 4H), 3.51 (tt, J=12.4, 2.8 Hz, 1H), 3.57(brs, 4H), 6.91 (d, J=2.4 Hz, 1H), 6.99 (dd, J=8.8, 2.4 Hz, 1H), 7.27(d, J=8.4 Hz, 1H).

81d4-[5-Morpholin-4-yl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine-1-carboxylicacid t-butyl ester

A mixture of4-[5-(nonafluorobutane-1-sulfonyloxy)-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine-1-carboxylicacid t-butyl ester (200 mg, 0.286 mmol) produced in Example (81c),morpholine (37.8 mg, 0.429 mmol), sodium t-butoxide (56.7 mg, 0.572mmol), tris(dibenzylideneacetone)dipalladium(0) (13.1 mg, 0.0143 mmol),2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (11.5 mg, 0.0286mmol) and xylene (3 mL) was stirred for 13 hours and 30 minutes at anexternal temperature of 100° C. under a nitrogen atmosphere. Thereaction mixture was filtered through Celite to remove insolublematerials, and the filtrate was concentrated under reduced pressure. Theresultant residue was purified by NH silica gel column chromatography(ethyl acetate/heptane) to give 103 mg of the title compound as a lightyellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.91 (s, 6H), 1.10 (s, 6H), 1.11-1.44 (m,6H), 1.48 (s, 9H), 2.82 (brs, 4H), 3.10-3.12 (m, 4H), 3.45 (tt, J=12.8,2.8 Hz, 1H), 3.83-3.85 (m, 4H), 6.62-6.68 (m, 2H), 7.12 (d, J=8.0 Hz,1H).

The 4H of piperazine ring could not be identified.

81e4-[3-piperazin-1-yl-4-(3,3,5,5-tetramethylcyclohexyl)phenyl]morpholine

A mixture of4-[5-morpholin-4-yl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine-1-carboxylicacid t-butyl ester (103 mg, 0.212 mmol) produced in Example (81d),trifluoroacetic acid (1 mL, 13.0 mmol) and dichloromethane (2 mL) wasstirred for 1 hour at room temperature. Ethyl acetate and saturatedaqueous solution of sodium hydrogencarbonate were added to the reactionmixture and extraction was performed with ethyl acetate. The separatedorganic layer was washed with water and brine in that order and thendried over anhydrous sodium sulfate. The desiccant was filtered off andthe filtrate was concentrated under reduced pressure. The resultantresidue was purified by silica gel column chromatography (ethylacetate/heptane) to give 42 mg of the title compound as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.91 (s, 6H), 1.11 (s, 6H), 1.12-1.45 (m,6H), 2.80-2.90 (m, 4H), 3.00-3.03 (m, 4H), 3.11-3.13 (m, 4H), 3.45 (tt,J=12.8, 2.8 Hz, 1H), 3.80-3.90 (m, 4H), 6.63 (dd, J=8.4, 2.8 Hz, 1H),6.68 (d, J=2.8 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H).

The 1H of NH could not be identified.

81f4-[3-(4-Butylpiperazin-1-yl)-4-(3,3,5,5-tetramethylcyclohexyl)phenyl]morpholinehydrochloride

To a mixture of4-[3-piperazin-1-yl-4-(3,3,5,5-tetramethylcyclohexyl)phenyl]morpholine(14 mg, 0.0363 mmol) produced in Example (81e), butyraldehyde (0.0097mL, 0.109 mmol) and tetrahydrofuran (0.5 mL) was added sodiumtriacetoxyborohydride (23 mg, 0.109 mmol), followed by stirring for 1hour and 30 minutes at room temperature. Saturated aqueous solution ofsodium hydrogencarbonate was added to the reaction mixture andextraction was performed with ethyl acetate. The solvent was distilledof by nitrogen stream to the separated organic layer. The resultantresidue was purified by NH silica gel column chromatography (ethylacetate/heptane) to give4-[3-(4-butylpiperazine-1-yl)-4-(3,3,5,5-tetramethylcyclohexyl)phenyl]morpholine.

¹H-NMR (400 MHz, CDCl₃) δ: 0.91 (s, 6H), 0.94 (t, J=7.2 Hz, 3H), 1.11(s, 6H), 1.13-1.54 (m, 10H), 2.39 (t, J=7.6 Hz, 2H), 2.59 (brs, 4H),2.92 (s, 4H), 3.10 (s, 4H), 3.43 (t, J=12.4 Hz, 1H), 3.84 (s, 4H), 6.63(d, J=8.0 Hz, 1H), 6.70 (s, 1H), 7.10 (d, J=8.0 Hz, 1H).

This compound was dissolved in dichloromethane, and a 4N solution ofhydrogen chloride in ethyl acetate was added. The solvent was distilledoff by nitrogen stream. Diethyl ether-hexane was added to the obtainedresidue to produce a solid, which was then triturated by sonication. Thesupernatant diethyl ether-hexane solution was removed and the resultingsolid was dried to give 17.2 mg of the title compound as a light redsolid.

MS m/e (ESI) 442 (MH⁺).

Example 821-[3-(4-Propylpiperazin-1-yl)-4-(3,3,5,5-tetramethylcyclohexyl)phenyl]ethanonehydrochloride

82a4-[5-Acetyl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine-1-carboxylicacid t-butyl ester

A mixture of4-[5-(nonafluorobutane-1-sulfonyloxy)-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine-1-carboxylicacid t-butyl ester (267 mg, 0.382 mmol) produced in Example (81c),tributyl(1-ethoxyvinyl)tin (0.16 mL, 0.458 mmol),dichlorobis(triphenylphosphine)palladium(II) (41 mg, 0.0573 mmol),lithium chloride (48.6 mg, 1.15 mmol) and dimethylformamide (3 mL) wasstirred for 6 hours and 10 minutes at an external temperature of 90° C.under a nitrogen atmosphere. Saturated aqueous solution of sodiumhydrogencarbonate and ethyl acetate were then added to the reactionmixture. The mixture was filtered through Celite, and the resultantfiltrate was concentrated under reduced pressure. The residue waspurified by NH silica gel column chromatography (ethyl acetate/heptane)to give 163 mg of the title compound as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.94 (s, 6H), 1.12 (s, 6H), 1.14-1.46 (m,6H), 1.49 (s, 9H), 2.56 (s, 3H), 2.76-2.92 (m, 4H), 3.61 (tt, J=12.4,2.8 Hz, 1H), 7.31 (d, J=7.6 Hz, 1H), 7.64-7.68 (m, 2H).

The 4H of piperazine ring could not be identified.

82b 1-[3-piperazin-1-yl-4-(3,3,5,5-tetramethylcyclohexyl)phenyl]ethanone

A mixture of4-[5-acetyl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine-1-carboxylicacid t-butyl ester (163 mg, 0.368 mmol) produced in Example (82a),diethyl ether (2 mL) and heptane (2 mL) was stirred at room temperature.A 4N solution of hydrogen chloride in ethyl acetate (2 mL, 8 mmol) wasadded thereto, and the mixture was stirred for 18 hours and 30 minutes.Saturated aqueous solution of sodium hydrogencarbonate was added to thereaction mixture and extraction was performed with diethyl ether. Theseparated organic layer was washed with water and brine in that order.The mixture was then filtered through Celite, and the filtrate wasconcentrated under reduced pressure. The resultant residue was purifiedby NH silica gel column chromatography (ethyl acetate/heptane) to give58 mg of the title compound as a light yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.94 (s, 6H), 1.13 (s, 6H), 1.14-1.46 (m,6H), 2.57 (s, 3H), 2.82-2.91 (m, 4H), 2.99-3.17 (m, 4H), 3.62 (tt,J=12.4, 2.8 Hz, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.64 (dd, J=8.0, 2.0 Hz,1H), 7.69 (d, J=2.0 Hz, 1H).

The 1H of NH could not be identified.

82c1-[3-(4-Propylpiperazin-1-yl)-4-(3,3,5,5-tetramethylcyclohexyl)phenyl]ethanonehydrochloride

To a mixture of1-[3-piperazin-1-yl-4-(3,3,5,5-tetramethylcyclohexyl)phenyl]ethanone (19mg, 0.0555 mmol) produced in Example (82b), propionaldehyde (0.0119 mL,0.166 mmol) and tetrahydrofuran (0.3 mL) was added sodiumtriacetoxyborohydride (35 mg, 0.166 mmol), followed by stirring for 1hour at room temperature. Saturated aqueous solution of sodiumhydrogencarbonate was added to the reaction mixture and extraction wasperformed with diethyl ether. The solvent was distilled off by nitrogenstream to the separated organic layer. The resultant residue waspurified by NH silica gel column chromatography (ethyl acetate/heptane)to give1-[3-(4-propylpiperazin-1-yl)-4-(3,3,5,5-tetramethylcyclohexyl)phenyl]ethanone.

¹H-NMR (400 MHz, CDCl₃) δ: 0.90-0.97 (m, 9H), 1.13 (s, 6H), 1.14-1.45(m, 8H), 2.34-2.40 (m, 2H), 2.56 (s, 3H), 2.60 (brs, 4H), 2.90-3.00 (m,4H), 3.59 (tt, J=12.4, 2.8 Hz, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.64 (dd,J=8.0, 2.0 Hz, 1H), 7.70 (d, J=2.0 Hz, 1H).

This compound was dissolved in dichloromethane, and a 4N solution ofhydrogen chloride in ethyl acetate was added. The solvent was distilledoff by nitrogen stream. Diethyl ether-heptane was added to the obtainedresidue to produce a solid, which was then triturated by sonication. Thesupernatant diethyl ether-heptane solution was removed and the resultingsolid was dried to give 15.5 mg of the title compound as a colorlesssolid.

MS m/e (ESI) 385 (MH⁺).

Example 831-[4-[2-(4,4-Diethylcyclohexyl)phenyl]piperazin-1-yl]butan-1-one

83a 1-[2-(4,4-Diethylcyclohexyl)phenyl]piperazine

A mixture of 4-[2-(4,4-dimethylcyclohexyl)phenyl]piperazine-1-carboxylicacid t-butyl ester (1.12 g, 2.80 mmol) produced in Example (38b),trifluoroacetic acid (10 mL, 130 mmol) and dichloromethane (10 mL) wasstirred for 10 minutes at an external temperature of 0° C., and thetemperature was raised to room temperature followed by stirring for 30minutes. Potassium carbonate was then gradually added to the reactionmixture to make the mixture basic. Then, ethyl acetate and water wereadded and extraction was performed with ethyl acetate.

The separated organic layer was washed with brine and dried overanhydrous magnesium sulfate. The desiccant was filtered off and then thefiltrate was concentrated under reduced pressure. The resultant residuewas purified by silica gel column chromatography(dichloromethane/methanol) to give 912 mg of the title compound as awhite solid.

MS m/e (ESI) 301 (MH⁺).

83b 1-[4-[2-(4,4-Diethylcyclohexyl)phenyl]piperazin-1-yl]butan-1-one

To a solution of 1-[2-(4,4-dimethylcyclohexyl)phenyl]piperazine (30 mg,0.10 mmol) produced in Example (83a) in tetrahydrofuran (1 mL) was addedtriethylamine (15 mg, 0.15 mmol), followed by stirring at an externaltemperature of 0° C. Butyryl chloride (0.015 mL, 0.14 mmol) was added tothe reaction mixture while stirring, and the stirring was continued for9 hours and 30 minutes at an external temperature of 0° C. Saturatedaqueous solution of sodium hydrogencarbonate was added to the reactionmixture and extraction was performed with ethyl acetate. The organiclayer was washed with water and filtered through Celite, and thefiltrate was concentrated. The resultant residue was purified by NHsilica gel column chromatography (ethyl acetate/heptane) to give 27 mgof the title compound as a yellow solid.

MS m/e (ESI) 371 (MH⁺).

Example 841-{4-[2-(4,4-Diethylcyclohexyl)-4-morpholin-4-ylphenyl]piperazin-1-yl}butan-2-onehydrochloride

84a4-[2-(4,4-Diethylcyclohexyl)-4-morpholin-4-yl)phenyl]piperazine-1-carboxylicacid t-butyl ester

To a solution of4-[4-bromo-2-(4,4-dimethylcyclohexyl)phenyl]piperazine-1-carboxylic acidt-butyl ester (500 mg, 1.0 mmol) produced in Example (38c) in xylene (10mL) were added morpholine (245 mg, 2.82 mmol), sodium t-butoxide (450mg, 4.68 mmol), tri-t-butylphosphonium tetrafluoroborate (340 mg, 1.17mmol) and palladium(II) acetate (105 mg, 0.47 mmol), followed bystirring for 1 hour at an external temperature of 100° C. under anitrogen atmosphere. The reaction mixture was air-cooled to roomtemperature and then filtered through Celite. The obtained filtrate wasconcentrated under reduced pressure, and the residue was partitionedbetween ethyl acetate and water. The obtained organic layer was washedwith brine and dried over anhydrous magnesium sulfate. The desiccant wasfiltered off and the obtained filtrate was distilled off under reducedpressure. The resultant residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give 573 mg of the titlecompound as a white solid.

84b 4-[3-(4,4-Diethylcyclohexyl)-4-piperazin-1-ylphenyl]morpholine

A mixture of4-[2-(4,4-dimethylcyclohexyl)-4-morpholin-4-yl]phenyl]piperazine-1-carboxylicacid t-butyl ester (573 mg, 1.18 mmol) produced in Example (84a),trifluoroacetic acid (10 mL, 130 mmol) and dichloromethane (10 mL) wasstirred for 10 minutes at an external temperature of 0° C., and then thestirring was continued for 30 minutes at room temperature. The reactionmixture was cooled in ice water, and potassium carbonate was addedthereto to make the mixture basic. Then, ethyl acetate and water wereadded and extraction was performed with ethyl acetate. The separatedorganic layer was washed with brine and dried over anhydrous magnesiumsulfate. The desiccant was filtered off and then the filtrate wasconcentrated under reduced pressure. The resultant residue was purifiedby NH silica gel column chromatography (ethyl acetate/hexane) to give354 mg of the title compound as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 0.75-0.85 (m, 6H), 1.16-1.68 (m, 13H),2.76-2.79 (m, 4H), 2.98-3.00 (m, 4H), 3.11-3.13 (m, 4H), 3.85-3.87 (m,4H), 6.70 (dd, J=8.8, 2.8 Hz, 1H), 6.81 (d, J=2.8 Hz, 1H), 7.05 (d,J=8.8 Hz, 1H).

The 1H of NH could not be identified.

84c1-[4-[2-(4,4-Diethylcyclohexyl)-4-morpholin-4-ylphenyl]piperazin-1-yl]butan-2-onehydrochloride

To a solution of4-[3-(4,4-dimethylcyclohexyl)-4-piperazin-1-ylphenyl]morpholine (20 mg,0.052 mmol) produced in Example (84b) in dimethylformamide (1 mL) wereadded potassium carbonate (11 mg, 0.078 mmol) and 1-bromo-2-butanone(9.4 mg, 0.063 mmol), followed by stirring for 2 hours and 5 minutes atan external temperature of 80° C. After air-cooling, water was added tothe reaction mixture and extraction was performed with ethyl acetate.The organic layer was washed with water and then filtered throughCelite, and the filtrate was concentrated. The resultant residue waspurified by NH silica gel column chromatography (ethyl acetate/heptane)to give1-[4-[2-(4,4-dimethylcyclohexyl)-4-morpholin-4-ylphenyl]piperazin-1-yl]butan-2-one.This compound was dissolved in ethyl acetate, and a 4N solution ofhydrogen chloride in ethyl acetate (0.020 mL, 0.080 mmol) was added. Thesolution was concentrated under reduced pressure, and then hexane wasadded to the obtained residue to produce a solid. The solid wastriturated by sonication and the supernatant hexane solution wasremoved. The obtained solid residue was dried under reduced pressure togive 25 mg of the title compound as a white solid.

MS m/e (ESI) 493 (MH⁺).

Example 851-[4-Methoxy-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-(tetrahydropyran-4-ylmethyl)piperazinehydrochloride

85a 4-Methoxy-1′-nitro-2-(3,3,5,5-tetramethylcyclohex-1′-enyl)benzene

To a solution of 3-iodo-4-nitroanisole (4.21 g, 15.1 mmol) in1,2-dimethoxyethane (50 mL) were added4,4,5,5-tetramethyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)[1,3,2]dioxaborolane(4.78 g, 18.1 mmol) produced in Example (4b), tripotassium phosphate(4.81 g, 22.7 mmol) and water (3 mL). Then,tetrakis(triphenylphosphine)palladium(0) (870 mg, 0.755 mmol) was addedto the mixture while stirring at room temperature under a nitrogenatmosphere. The mixture was then further stirred for 13 hours at anexternal temperature of 70° C. To the reaction mixture were addedtetrakis(triphenylphosphine)palladium(0) (870 mg, 0.755 mmol) and water(3 mL), followed by stirring for 26 hours at an external temperature of100° C. The reaction mixture was cooled, and then ethyl acetate wasadded and the mixture was filtered through Celite. The filtrate wasconcentrated to give a residue, which was subjected to extraction withethyl acetate, and the organic layer was washed with brine. The organiclayer was dried over anhydrous magnesium sulfate and then the desiccantwas filtered off and the filtrate was concentrated under reducedpressure. The resultant residue was purified by silica gel columnchromatography (ethyl acetate/heptane) to give 1.5 g of the titlecompound as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 1.05 (s, 6H), 1.07 (s, 6H), 1.41 (s, 2H),1.99 (d, J=1.6 Hz, 2H), 3.88 (s, 3H), 5.35 (m, 1H), 6.68 (d, J=2.4 Hz,1H), 6.81 (dd, J=9.2, 2.4 Hz, 1H), 7.91 (d, J=9.2 Hz, 1H).

85b 4-Methoxy-2-(3,3,5,5-tetramethylcyclohexyl)phenylamine

A mixture of4-methoxy-1-nitro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)benzene (1.0 g,3.46 mmol) produced in Example (85a), 10% palladium on carbon (500 mg,wet), methanol (8 mL) and tetrahydrofuran (2 mL) was stirred overnightat room temperature and atmospheric pressure under a hydrogenatmosphere. The mixture was filtered through Celite to remove thecatalyst, and the filtrate was concentrated. A crude product of thetitle compound was obtained as a brown oil. The crude product was usedwithout purification for the following reaction.

85c 1-[4-Methoxy-2-(3.3, 5,5-tetramethylcyclohexyl)phenyl]piperazine

A mixture of the crude product of4-methoxy-2-(3,3,5,5-tetramethylcyclohexyl)phenylamine produced inExample (85b), bis(2-chloroethyl)amine hydrochloride (770 mg, 4.33 mmol)and 1,2-dichlorobenzene (10 ml) was stirred for 2 hours at an externaltemperature of 220° C. During the reaction, the excess hydrogen chloridegas in the reactor was removed several times with nitrogen gas.Bis(2-chloroethyl)amine hydrochloride (180 mg, 1.01 mmol) was then addedand the mixture was stirred for 1 hour under the same conditions. Thereaction mixture was cooled to room temperature, saturated aqueoussolution of sodium hydrogencarbonate was added and extraction wasperformed with chloroform. The aqueous layer was again extracted withchloroform, and the organic layers were combined, washed with brine andthen dried over anhydrous magnesium sulfate. The desiccant was filteredoff and the filtrate was concentrated under reduced pressure. Theresultant residue was purified by NH silica gel column chromatography(ethyl acetate/heptane) to give 660 mg of the title compound as a brownsolid.

¹H-NMR (400 MHz, CDCl₃) δ: 0.92 (s, 6H), 1.12 (s, 6H), 1.15-1.34 (m,4H), 1.42-1.45 (m, 2H), 2.78-2.81 (m, 4H), 2.99-3.02 (m, 4H), 3.63 (tt,J=13, 2.8 Hz, 1H), 3.78 (s, 3H), 6.69 (dd, J=8.8, 2.8 Hz, 1H), 6.77 (d,J=2.8 Hz, 1H), 7.07 (d, J=8.8 Hz, 1H).

85d1-[4-Methoxy-2-(3,355-tetramethylcyclohexyl)phenyl]-4-(tetrahydropyran-4-ylmethyl)piperazinehydrochloride

To a solution of1-[4-methoxy-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (10 mg,0.030 mmol) produced in Example (85c) in tetrahydrofuran (1 mL) wereadded tetrahydropyranyl-4-carbaldehyde (5.2 mg, 0.045 mmol), sodiumtriacetoxyborohydride (13 mg, 0.061 mmol) and acetic acid (1.8 mg, 0.030mmol) in that order, followed by stirring for 60 minutes at roomtemperature. Saturated aqueous solution of sodium hydrogencarbonate wasadded to the reaction mixture, extraction was performed with ethylacetate, and the organic layer was concentrated. The resultant residuewas purified by NH silica gel column chromatography (ethylacetate/heptane) to give1-[4-methoxy-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-(tetrahydropyran-4-ylmethyl)piperazine.

¹H-NMR (400 MHz, CDCl₃) δ: 0.92 (s, 6H), 1.12 (s, 6H), 1.15-1.35 (m,6H), 1.41-1.48 (m, 2H), 1.68-1.72 (m, 2H), 1.74-1.85 (m, 1H), 2.25 (d,J=7.2 Hz, 2H), 2.55 (brs, 4H), 2.84 (brs, 4H), 3.39 (ddd, J=12, 12, 2.0Hz, 2H), 3.60 (tt, J=12, 2.8 Hz, 1H), 3.78 (s, 3H), 3.97 (ddd, J=12,2.4, 2.0 Hz, 2H), 6.68 (dd, J=8.8, 2.8 Hz, 1H), 6.77 (d, J=2.8 Hz, 1H),7.07 (d, J=8.8 Hz, 1H).

The obtained compound was dissolved in ethyl acetate, and a 4N solutionof hydrogen chloride in ethyl acetate (0.010 mL, 0.040 mmol) was added.The solution was concentrated and hexane was added to the obtainedresidue to produce a solid, which was then triturated by sonication. Thesupernatant hexane solution was removed, and the solid residue was driedunder reduced pressure to give 13.6 mg of the title compound as a whitesolid.

MS m/e (ESI) 429 (MH⁺).

Example 861-Butyl-4-[4-methoxy-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

To a solution of1-[4-methoxy-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (10 mg,0.030 mmol) produced in Example (85c) in tetrahydrofuran (1 mL) wereadded butyraldehyde (3.3 mg, 0.045 mmol), sodium triacetoxyborohydride(13 mg, 0.061 mmol) and acetic acid (1.8 mg, 0.030 mmol) in that order,followed by stirring for 60 minutes at room temperature. Saturatedaqueous solution of sodium hydrogencarbonate was added to the reactionmixture, extraction was performed with ethyl acetate, and the organiclayer was concentrated. The resultant residue was purified by NH silicagel column chromatography (ethyl acetate/heptane) to give1-butyl-4-[4-methoxy-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine.

¹H-NMR (400 MHz, CDCl₃) δ: 0.92 (s, 6H), 0.94 (t, J=7.2 Hz, 3H), 1.12(s, 6H), 1.15-1.54 (m, 10H), 2.34-2.40 (m, 2H), 2.57 (br, 4H), 2.87 (br,4H), 3.59 (tt, J=12, 2.8 Hz, 1H), 3.77 (s, 3H), 6.67 (dd, J=8.8, 3.2 Hz,1H), 6.75 (d, J=3.2 Hz, 1H), 7.08 (d, J=8.8 Hz, 1H).

The obtained compound was dissolved in ethyl acetate, and a 4N solutionof hydrogen chloride in ethyl acetate (0.010 mL, 0.040 mmol) was added.The solution was concentrated and hexane was added to the obtainedresidue to produce a solid, which was then triturated by sonication. Thesupernatant hexane solution was removed, and the solid residue was driedunder reduced pressure to give 8.6 mg of the title compound as a whitesolid.

MS m/e (ESI) 387 (MH⁺).

Example 871-[4,5-Dimethoxy-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-isobutylpiperazineehydrochloride

87a 1-Bromo-4,5-dimethoxy-2-nitrobenzene

A mixture of concentrated nitric acid (14 mL) and acetic acid (42 mL)was cooled to 110° C. while stirring, and then4-bromo-1,2-dimethoxybenzene (2 g, 9.21 mmol) was gradually added to thestirred mixture. The reaction mixture was warmed to 15° C., and stirringwas continued for 60 minutes. The reaction mixture was cooled to 0° C.and stirred while adding ice water, and then extraction was performedwith ether. The obtained organic layer was neutralized with saturatedaqueous solution of sodium hydrogencarbonate and potassium carbonate,and then washed with water. After drying the organic layer overanhydrous magnesium sulfate, the desiccant was filtered off and thefiltrate was concentrated under reduced pressure. The obtained crudeproduct was recrystallized from ethanol to give 2.09 g of the titlecompound as light yellow crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 3.94 (s, 3H), 3.97 (s, 3H), 7.12 (s, 1H),7.57 (s, 1H).

87b 4,5-Dimethoxy-1-nitro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)benzene

To a solution of 1-bromo-4,5-dimethoxy-2-nitrobenzene (1.06 g, 4.04mmol) produced in Example (87a) in 1,2-dimethoxyethane (30 mL) wereadded4,4,5,5-tetramethyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)[1,3,2]dioxaborolane(1.28 g, 4.85 mmol) produced in Example (4b), tripotassium phosphate(1.29 g, 6.06 mmol) and water (1.5 mL).Tetrakis(triphenylphosphine)palladium (230 mg, 0.20 mmol) was then addedto the mixture while stirring at room temperature under a nitrogenatmosphere. The mixture was then stirred for 13 hours at an externaltemperature of 70° C., and stirring was continued for 3 hours at anexternal temperature of 100° C. Tetrakis(triphenylphosphine)palladium(0)(230 mg, 0.20 mmol) and water (2 mL) were added to the reaction mixture,and it was further stirred for 9 hours at an external temperature of100° C. and then for 11 hours at an external temperature of 70° C. Aftercooling the reaction mixture, ethyl acetate was added and the mixturewas filtered through Celite. The filtrate was concentrated and extractedwith ethyl acetate, and the obtained organic layer was washed withbrine. The organic layer was then dried over anhydrous magnesiumsulfate, the desiccant was filtered off, and the filtrate wasconcentrated under reduced pressure. The resultant residue was purifiedby silica gel column chromatography (ethyl acetate/heptane) to give 1.1g of the title compound as a brown oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.06 (s, 6H), 1.07 (s, 6H), 1.42 (s, 2H),1.99 (d, J=1.6 Hz, 2H), 3.93 (s, 3H), 3.96 (s, 3H), 5.32 (m, 1H), 6.60(s, 1H), 7.47 (s, 1H).

87c 4,5-Dimethoxy-2-(3,3,5,5-tetramethylcyclohexyl)phenylamine

A mixture of4,5-dimethoxy-1-nitro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)benzene (1.0g, 3.13 mmol) produced in Example (87b), 10% palladium on carbon (500mg, wet), methanol (8 mL) and tetrahydrofuran (2 mL) was stirred for 13hours at room temperature and atmospheric pressure under a hydrogenatmosphere. The mixture was filtered through Celite to remove thecatalyst, and the filtrate was concentrated. A crude product of thetitle compound was obtained as a yellow oil. The crude product was usedwithout purification for the following reaction.

87d 1-[4,5-Dimethoxy-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine

A mixture of the crude product of4,5-dimethoxy-2-(3,3,5,5-tetramethylcyclohexyl)phenylamine produced inExample (87c), bis(2-chloroethyl)amine hydrochloride (700 mg, 3.91 mmol)and 1,2-dichlorobenzene (10 ml) was stirred for 2 hours at an externaltemperature of 220° C. During the reaction, nitrogen gas was blown inseveral times to remove the excess hydrogen chloride gas from thereactor. The reaction mixture was cooled to room temperature, saturatedaqueous solution of sodium hydrogencarbonate was added and extractionwas performed with chloroform. The aqueous layer was again extractedwith chloroform, and the organic layers were combined, washed with brineand then dried over anhydrous magnesium sulfate. The desiccant wasfiltered off and the filtrate was concentrated under reduced pressure.The resultant residue was purified by NH silica gel columnchromatography (ethyl acetate/heptane) to give 490 mg of the titlecompound as a brown oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.93 (s, 6H), 1.13 (s, 6H), 1.15-1.43 (m,6H), 2.80-2.83 (m, 4H), 3.00-3.03 (m, 4H), 3.63 (tt, J=13, 2.8 Hz, 1H),3.85 (s, 3H), 3.87 (s, 3H), 6.72 (s, 1H), 6.73 (s, 1H).

87e1-[4,5-Dimethoxy-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-isobutylpiperazineehydrochloride

To a solution of the1-[4,5-dimethoxy-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (10mg, 0.028 mmol) produced in Example (87d) in tetrahydrofuran (1 mL) wereadded isobutyraldehyde (3.0 mg, 0.042 mmol), sodiumtriacetoxyborohydride (12 mg, 0.057 mmol) and acetic acid (1.7 mg, 0.028mmol) in that order, followed by stirring for 60 minutes at roomtemperature. Saturated aqueous solution of sodium hydrogencarbonate wasadded to the reaction mixture, extraction was performed with ethylacetate, and the organic layer was concentrated. The resultant residuewas purified by NH silica gel column chromatography (ethylacetate/heptane) to give1-[4,5-dimethoxy-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-isobutylpiperazinee.

¹H-NMR (400 MHz, CDCl₃) δ: 0.86-1.44 (m, 6H), 0.93 (s, 6H), 0.93 (d,J=6.8 Hz, 6H), 1.12 (s, 6H), 1.82 (m, 1H), 2.15 (d, J=7.6 Hz, 2H), 2.55(br, 4H), 2.87 (br, 4H), 3.61 (tt, J=13, 2.8 Hz, 1H), 3.84 (s, 3H), 3.87(s, 3H), 6.71 (s, 1H), 6.76 (s, 1H).

The obtained compound was dissolved in ethyl acetate, and a 4N solutionof hydrogen chloride in ethyl acetate (0.010 mL, 0.040 mmol) was added.The solution was concentrated, and hexane was added to the obtainedresidue to produce a solid, which was then triturated by sonication. Thesupernatant hexane solution was removed and the solid residue was driedunder reduced pressure to give 10.3 mg of the title compound as a whitesolid.

MS m/e (ESI) 417 (MH⁺).

Example 881-Butyl-4-[4-nitro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazinehydrochloride

88a 4-(2-Chloro-4-nitrophenyl)piperazine-1-carboxylic acid t-butyl ester

A mixture of 3-chloro-4-fluoronitrobenzene (5 g, 27.1 mmol),1-piperazinecarboxylic acid t-butyl ester (5 g, 26.8 mmol) anddimethylformamide (10 mL) was stirred for 3 hours and 30 minutes at anexternal temperature of 130° C. After adding water to the air-cooledreaction mixture, extraction was performed 3 times with chloroform. Theorganic layers were washed with brine and dried over anhydrous magnesiumsulfate. The desiccant was filtered off and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/heptane) to give 5.93 g of thetitle compound as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 1.49 (s, 9H), 3.15 (dd, J=5.2, 4.8 Hz, 4H),3.63 (dd, J=5.2, 4.8 Hz, 4H), 7.04 (d, J=8.8 Hz, 1H), 8.11 (dd, J=8.8,2.8 Hz, 1H), 8.27 (d, J=2.8 Hz, 1H).

88b4-[4-Nitro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazine-1-carboxylicacid t-butyl ester

To a solution of 4-(2-chloro-4-nitrophenyl)piperazine-1-carboxylic acidt-butyl ester (5.93 g, 17.3 mmol) produced in Example (88a) in1,2-dimethoxyethane (70 mL) were added4,4,5,5-tetramethyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)[1,3,2]dioxaborolane(5.5 g, 20.8 mmol) produced in Example (4b), tripotassium phosphate(5.51 g, 26 mmol) and water (3 mL).Tetrakis(triphenylphosphine)palladium(0) (1.0 g, 0.865 mmol) was addedto the mixture while stirring at room temperature under a nitrogenatmosphere. The mixture was then stirred for 3 hours at an externaltemperature of 80° C., and then for 7 hours at an external temperatureof 100° C. Tetrakis(triphenylphosphine)palladium(0) (830 mg, 0.718 mmol)was added to the reaction mixture, and stirring was continued for 22hours and 30 minutes. Ethyl acetate was added to the reaction mixture,which was then filtered through Celite. The filtrate was concentratedand the resultant residue was extracted with ethyl acetate, and theobtained organic layer was washed with water and brine. The organiclayer was dried over anhydrous magnesium sulfate and then the desiccantwas filtered off and the filtrate was concentrated under reducedpressure. The resultant residue was purified by silica gel columnchromatography (ethyl acetate/heptane) to give 1.08 g of the titlecompound as an orange oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.03 (s, 6H), 1.10 (s, 6H), 1.42 (s, 2H),1.49 (s, 9H), 2.11 (s, 2H), 3.07-3.10 (m, 4H), 3.53-3.56 (m, 4H), 5.67(s, 1H), 6.94 (d, J=8.8 Hz, 1H), 7.93 (d, J=2.8 Hz, 1H), 8.06 (dd,J=8.8, 2.8 Hz, 1H).

88c 1-[4-Nitro-2-(3,3,5,5-tetramethylcylohex-1-enyl)phenyl]piperazine

A solution of4-[4-nitro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazine-1-carboxylicacid t-butyl ester (300 mg, 0.676 mmol) produced in Example (88b) indichloromethane (3 mL) was stirred at an external temperature of 0° C.Trifluoroacetic acid (1 mL) was gradually added dropwise thereto over aperiod of 15 minutes. The reaction mixture was allowed to warm to roomtemperature while stirring for 90 minutes. While cooled in an ice bath,saturated aqueous solution of sodium hydrogencarbonate to the mixture tomake the mixture basic. Extraction was performed with ethyl acetate, andthe separated organic layer was washed with water and then dried overanhydrous magnesium sulfate. The desiccant was filtered off and thefiltrate was concentrated under reduced pressure. The resultant residuewas purified by NH silica gel column chromatography (ethylacetate/heptane) to give 180 mg of the title compound as a light yellowsolid.

88d1-Butyl-4-[4-nitro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazinehydrochloride

To a solution of1-[4-nitro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazine (10mg, 0.029 mmol) produced in Example (88c) in tetrahydrofuran (1 mL) wereadded butyraldehyde (3.2 mg, 0.044 mmol), sodium triacetoxyborohydride(12 mg, 0.058 mmol) and acetic acid (2 mg, 0.029 mmol) in that order,followed by stirring for 3 hours at room temperature. Water was added tothe reaction mixture, extraction was performed with ethyl acetate, andthe organic layer was concentrated. The resultant residue was purifiedby NH silica gel column chromatography (ethyl acetate/heptane) to give1-butyl-4-[4-nitro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazine.

¹H-NMR (400 MHz, CDCl₃) δ: 0.94 (t, J=7.2 Hz, 3H), 1.03 (s, 6H), 1.10(s, 6H), 1.25 (m, 1H), 1.32-1.38 (m, 2H), 1.43-1.53 (m, 2H), 1.65 (m,1H), 2.11 (d, J=1.6 Hz, 2H), 2.36-2.40 (m, 2H), 2.56 (br, 4H), 3.19 (br,4H), 5.67 (t, J=1.6 Hz, 1H), 6.94 (d, J=9.2 Hz, 1H), 7.92 (d, J=2.8 Hz,1H), 8.04 (dd, J=9.2, 2.8 Hz, 1H).

The obtained compound was dissolved in ethyl acetate, and a 4N solutionof hydrogen chloride in ethyl acetate (0.010 mL, 0.040 mmol) was added.The solution was concentrated, and hexane was added to the obtainedresidue to produce a solid, which was then triturated by sonication. Thesupernatant hexane solution was removed and the residue was concentratedto give 6.3 mg of the title compound as a white solid.

MS m/e (ESI) 400 (MH⁺).

Example 891-Cyclobutyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

To a solution of 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine(20 mg, 0.067 mmol) produced in Example (8b) in tetrahydrofuran (1 mL)were added cyclobutanone (7.0 mg, 0.1 mmol), sodiumtriacetoxyborohydride (28 mg, 0.13 mmol) and acetic acid (4 mg, 0.067mmol) in that order, followed by stirring for 30 minutes at roomtemperature. Saturated aqueous solution of sodium hydrogencarbonate wasadded to the reaction mixture, extraction was performed with ethylacetate, and the organic layer was concentrated. The resultant residuewas purified by NH silica gel column chromatography (ethylacetate/heptane) to give1-cyclobutyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine. Theobtained compound was dissolved in ethyl acetate, and a 4N solution ofhydrogen chloride in ethyl acetate (0.025 mL, 0.100 mmol) was added. Thesolution was concentrated, and hexane was added to the obtained residueto produce a solid. The solid was triturated by sonication and thesupernatant hexane solution was removed. The solid residue was driedunder reduced pressure to give 17.6 mg of the title compound as a whitesolid.

MS m/e (ESI) 355 (MH⁺).

Example 901-Cyclopropyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

To a solution of 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine(30 mg, 0.1 mmol) produced in Example (8b) in methanol (3 mL) were added[(1-ethoxycyclopropyl)oxy]trimethylsilane (105 mg, 0.6 mmol), sodiumcyanotrihydroborate (28.3 mg, 0.45 mmol), acetic acid (60.1 mg, 1 mmol)and molecular sieves 3A (50 mg) in that order, followed by stirring for5 hours and 30 minutes at an external temperature of 80° C. Ethylacetate was added to the reaction mixture, which was filtered throughCelite, and the filtrate was concentrated. Water was then added to theresidue, extraction was performed with ethyl acetate, and the organiclayer was washed with 2N aqueous solution of sodium hydroxide and brine.The organic layer was dried over magnesium sulfate, the desiccant wasfiltered off, and then the filtrate was concentrated. The resultantresidue was purified by NH silica gel column chromatography (ethylacetate/heptane) to give1-cyclopropyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine as awhite solid. The obtained compound was dissolved in ethyl acetate, and a4N solution of hydrogen chloride in ethyl acetate (0.040 mL, 0.160 mmol)was added. The solution was concentrated, and hexane was added to theobtained residue to produce a solid, which was then triturated bysonication. The supernatant hexane solution was removed and theresulting solid residue was dried under reduced pressure to give 37.7 mgof the title compound as a white solid.

MS m/e (ESI) 341 (MH⁺).

Example 912-{4-[2-(3,3,5,5-Tetramethylcyclohexyl)phenyl]piperazin-1-ylmethyl}cyclopropanecarboxylicacid ethyl ester hydrochloride

1-[2-(3,3,5,5-Tetramethylcyclohexyl)phenyl]piperazine (2.1 g, 7 mmol)produced in Example (8b) was used as a starting material. Reaction wasconducted in a manner similar to Example (4g), using2-formyl-1-cyclopropanecarboxylic acid ethyl ester (cis/trans mixture,predominantly trans) instead of butyraldehyde, and similar treatment wascarried out to give 2.4 g of2-{4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazin-1-ylmethyl}cyclopropanecarboxylicacid ethyl ester as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.77-0.81 (m, 1H), 0.92 (s, 6H), 1.12 (s,6H), 1.25-1.36 (m, 9H), 1.37-1.50 (m, 3H), 2.33-2.84 (m, 6H), 2.94 (t,J=4.8 Hz, 4H), 3.56 (tt, J=12.8, 2.8 Hz, 1H), 4.10-4.19 (m, 2H),7.04-7.18 (m, 3H), 7.22 (d, J=7.6 Hz, 1H).

A 48 mg portion of this compound was converted to a hydrochloride by amethod similar to in Example (4g) to give 52 mg of the title compound asa colorless solid.

MS m/e (ESI) 427 (MH⁺).

Example 92trans-1-(2-Methoxymethylcyclopropylmethyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

92acis-(2-{4-[2-(3,3,5,5-Tetramethylcyclohexyl)phenyl]piperazin-1-ylmethyl}cyclopropyl)methanolandtrans-(2-{4-[2-(3,3,5,5-Tetramethylcyclohexyl)phenyl]piperazin-1-ylmethyl}cyclopropyl)methanol

Lithium aluminum hydride (178 mg, 4.68 mmol) was suspended in anhydroustetrahydrofuran (15 mL), and the suspension was stirred at roomtemperature under a nitrogen atmosphere. To the suspension was added asolution of2-{4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazin-1-ylmethyl}cyclopropanecarboxylicacid ethyl ester (1 g, 2.34 mmol) produced in Example (91) in anhydroustetrahydrofuran (15 mL), followed by stirring for 1 hour and 30 minutesat room temperature. Sodium fluoride (1 g) was added to the reactionmixture, and water (0.4 mL) was gradually added while blowing nitrogen.After stirring for 1 hour, the insoluble materials were filtered off andthe filtrate was concentrated under reduced pressure. The resultantresidue was purified by NH silica gel column chromatography (ethylacetate/heptane). This procedure gave 173 mg ofcis-(2-{4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazin-1-ylmethyl}cyclopropyl)methanolas colorless crystals, and 596 mg oftrans-(2-{4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazin-1-ylmethyl}cyclopropyl)methanolas a colorless oil.

cis: ¹H-NMR (400 MHz, CDCl₃) δ: 0.26 (q, J=4.8H, 1H), 0.83-0.88 (m, 1H),0.92 (s, 6H), 1.12 (s, 6H), 1.15-1.46 (m, 8H), 2.24 (dd, J=13.2, 13.2Hz, 1H), 2.60 (br, 4H), 2.75 (dd, J=13.2, 5.2 Hz, 1H), 2.87-3.00 (m,4H), 3.12 (dd, J=13.2, 13.2 Hz, 1H), 3.55 (tt, J=12.8, 2.8 Hz, 1H), 4.02(dd, J=13.2, 5.2 Hz, 1H), 7.04-7.16 (m, 3H), 7.21 (dd, J=7.6, 1.6 Hz,1H).

The 1H of OH could not be identified.

trans: ¹H-NMR (400 MHz, CDCl₃) δ: 0.41-0.47 (m, 1H), 0.49-0.55 (m, 1H),0.90 (s, 6H), 1.12 (s, 6H), 1.15-1.47 (m, 8H), 2.30 (dd, J=12.8, 7.2 Hz,1H), 2.44 (dd, J=12.8, 6.4 Hz, 1H), 2.70 (br, 4H), 2.94 (t, J=4.8 Hz,4H), 3.45-3.60 (m, 3H), 7.04-7.17 (m, 3H), 7.21 (dd, J=7.2, 1.6 Hz, 1H).

The 1H of OH could not be identified.

92btrans-1-(2-Methoxymethylcyclopropylmethyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

Sodium hydride (60%, oily) (31 mg, 0.78 mmol) was suspended indimethylformamide (3 mL), and the suspension was stirred at roomtemperature under a nitrogen atmosphere. To the suspension was added asolution oftrans-(2-{4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazin-1-ylmethyl}cyclopropyl)methanol(60 mg, 0.156 mmol) produced in Example (91a) in dimethylformamide (3mL), and the mixture was stirred for 30 minutes under the sameconditions. The reaction mixture was cooled in ice water, and theniodomethane (0.015 mL, 0.241 mmol) was added. The reaction mixture wasthen stirred for 3 hours and 30 minutes while increasing the temperatureto room temperature. The reaction mixture was cooled at an externaltemperature of 0° C., and water was carefully added while blowingnitrogen. Then, ethyl acetate and water were added thereto andextraction was performed with ethyl acetate. The separated organic layerwas washed twice with water and then once with brine, and dried overanhydrous sodium sulfate. The desiccant was filtered off and thefiltrate was concentrated under reduced pressure. The resultant residuewas purified by NH silica gel column chromatography (ethylacetate/heptane) to give 28 mg oftrans-1-(2-methoxymethylcyclopropylmethyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazineas a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.42-0.48 (m, 1H), 0.49-0.55 (m, 1H),0.80-0.96 (m, 2H), 0.92 (s, 6H), 1.12 (s, 6H), 1.13-1.35 (m, 4H),1.40-1.48 (m, 2H), 2.36 (dd, J=12.8, 6.8 Hz, 1H), 2.39 (dd, J=12.8, 6.8Hz, 1H), 2.66 (br, 4H), 2.94 (t, J=5.2 Hz, 4H), 3.22 (dd, J=10.0, 7.2Hz, 1H), 3.32 (dd, J=10.0, 6.4 Hz, 1H), 3.34 (s, 3H), 3.57 (tt, J=12.8,2.8 Hz, 1H), 7.04-7.17 (m, 3H), 7.21 (dd, J=7.2, 1.2 Hz, 1H).

This compound was dissolved in dichloromethane, and a 4N solution ofhydrogen chloride in ethyl acetate was added. Nitrogen was blown to thesolution to remove the solvent. Diethyl ether was added to the obtainedresidue to produce a solid, which was then triturated by sonication. Thesupernatant diethyl ether solution was removed and the resulting solidresidue was dried by blowing nitrogen, to give 13 mg of the titlecompound as a white solid.

MS m/e (ESI) 399 (MH⁺).

Example 93trans-1-(2-Fluoromethylcyclopropylmethyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

To a solution oftrans-(2-{4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazin-1-ylmethyl}cyclopropyl)methanol(60 mg, 0.156 mmol) produced in Example (92a) in dichloromethane (5 mL)was added diethylaminosulfur trifluoride (DAST) (0.052 mL, 0.394 mmol),followed by stirring for 2 hours at room temperature under a nitrogenatmosphere. The reaction mixture was cooled at an external temperatureof 0° C., saturated aqueous solution of sodium hydrogencarbonate wasadded, and the mixture was stirred. Then, ethyl acetate and water wereadded thereto and extraction was performed with ethyl acetate. Theseparated organic layer was washed with brine and then dried overanhydrous sodium sulfate. The desiccant was filtered off and thefiltrate was concentrated under reduced pressure. The resultant residuewas purified by NH silica gel column chromatography (ethylacetate/heptane) to give 17 mg oftrans-1-(2-fluoromethylcyclopropylmethyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazineas a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.50-0.64 (m, 2H), 0.92 (s, 6H), 0.93-1.03(m, 1H), 1.05-1.47 (m, 13H), 2.32 (dd, J=12.8, 6.8 Hz, 1H), 2.45 (dd,J=12.8, 6.0 Hz, 1H), 2.69 (br, 4H), 2.94 (t, J=4.8 Hz, 4H), 3.56 (tt,J=12.8, 2.8 Hz, 1H), 4.21 (ddd, J=48.8, 9.6, 7.2 Hz, 1H), 4.34 (ddd,J=48.8, 9.6, 7.2 Hz, 1H), 7.04-7.17 (m, 3H), 7.21 (d, J=7.2, 1H).

This compound was dissolved in dichloromethane, and a 4N solution ofhydrogen chloride in ethyl acetate was added. Nitrogen was then blown tothe solution to remove the solvent. Diethyl ether was added to theobtained residue to produce a solid, which was then triturated bysonication. The supernatant diethyl ether solution was removed, and theobtained solid residue was dried by blowing nitrogen, to give 16 mg ofthe title compound as a white solid.

MS m/e (ESI), 387 (MH⁺).

Example 94trans-(2-{4-[2-(3,3,5,5-Tetramethylcyclohexyl)phenyl]piperazin-1-ylmethyl}cyclopropyl)acetonitrilehydrochloride

94atrans-(2-{4-[2-(3,3,5,5-Tetramethylcyclohexyl)phenyl]piperazin-1-ylmethyl}cyclopropyl)acetonitrileandtrans-1-(2-Chloromethylcyclopropylmethyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine

A solution oftrans-(2-{4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazin-1-ylmethyl}cyclopropyl)methanol(60 mg, 0.156 mmol) produced in Example (92a) in dichloromethane (5 mL)was stirred at an external temperature of 0° C. under a nitrogenatmosphere. Triethylamine (0.065 mL, 0.468 mmol) and methanesulfonylchloride (0.018 mL, 0.233 mmol) were added in that order to the mixture,followed by stirring for 30 minutes under the same conditions. Saturatedaqueous solution of ammonium chloride was added to the reaction mixture,which was then washed with ethyl acetate and water and extracted withethyl acetate. The separated organic layer was washed with brine andthen dried over anhydrous sodium sulfate. The desiccant was filtered offand the filtrate was concentrated under reduced pressure. The resultantresidue was dissolved again in dimethylsulfoxide (3 mL), and thentetrabutylammonium iodide (12 mg, 0.032 mmol) and potassium cyanide (34mg, 0.522 mmol) were added thereto and the mixture was stirred for 2hours at an external temperature of 70° C. Ethyl acetate and water wereadded to the reaction mixture and extraction was performed with ethylacetate. The separated organic layer was washed twice with water andthen once with brine, and dried over anhydrous sodium sulfate. Thedesiccant was filtered off and the filtrate was concentrated underreduced pressure. The resultant residue was purified by NH silica gelcolumn chromatography (ethyl acetate/heptane) to give 8 mg oftrans-(2-{4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazin-1-ylmethyl}cyclopropyl)acetonitrileas a colorless oil, and 19 mg oftrans-1-(2-chloromethylcyclopropylmethyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazineas a colorless oil.

trans-(2-{4-[2-(3,3,5,5-Tetramethylcyclohexyl)phenyl]piperazin-1-ylmethyl}cyclopropyl)acetonitrile:

¹H-NMR (400 MHz, CDCl₃) δ: 0.53-0.65 (m, 2H), 0.87-1.00 (m, 8H), 1.12(s, 6H), 1.22-1.47 (m, 6H), 2.30-2.50 (m, 4H), 2.67 (br, 4H), 2.94 (t,J=4.8 Hz, 4H), 3.56 (tt J=12.8, 2.8 Hz, 1H), 7.04-7.17 (m, 3H), 7.21(dd, J=7.2, 1.6 Hz, 1H).

trans-1-(2-Chloromethylcyclopropylmethyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine:

¹H-NMR (400 MHz, CDCl₃) δ: 0.55-0.66 (m, 2H), 0.92 (s, 6H), 0.94-1.11(m, 2H), 1.12 (s, 6H), 1.13-1.46 (m, 6H), 2.33 (dd, J=12.8, 6.8 Hz, 1H),2.45 (dd, J=12.4, 6.4 Hz, 1H), 2.68 (br, 4H), 2.94 (t, J=4.8 Hz, 4H),3.47 (dd, J=11.2, 7.6 Hz, 1H), 3.50 (dd, J=11.2, 7.6 Hz, 1H), 3.56 (tt,J=12.8, 2.8 Hz, 1H), 7.04-7.17 (m, 3H), 7.21 (dd, J=7.6, 1.2 Hz, 1H).

94btrans-(2-[4-[2-(3,3,5,5-Tetramethylcyclohexyl)phenyl]piperazin-1-ylmethyl]cyclopropyl)acetonitrilehydrochloride

Totrans-(2-{4-[2-(3,3,5,5-Tetramethylcyclohexyl)phenyl]piperazin-1-ylmethyl}cyclopropyl)acetonitrile(8 mg) produced in Example (94a) dissolved in dichloromethane was addeda 4N solution of hydrogen chloride in ethyl acetate. Nitrogen was thenblown to the solution to remove the solvent. Diethyl ether was added tothe obtained residue to produce a solid, which was then triturated bysonication. The supernatant diethyl ether solution was removed and theresulting solid residue was dried by blowing nitrogen, to give 8 mg ofthe title compound as a light brown solid.

MS m/e (ESI) 394 (MH⁺).

Example 95trans-1-(2-Chloromethylcyclopropnlmethyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

Totrans-1-(2-chloromethylcyclopropylmethyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine(19 mg) produced in Example (94a) dissolved in dichloromethane was addeda 4N solution of hydrogen chloride in ethyl acetate. Nitrogen was thenblown to the solution to remove the solvent. Diethyl ether was added tothe obtained residue to produce a solid, which was then triturated bysonication. The supernatant diethyl ether solution was removed and theobtained solid residue was dried by blowing nitrogen, to give 22 mg ofthe title compound as a light red solid.

MS m/e (ESI) 403 (MH⁺).

Example 961-(2-Methylcyclopropylmethyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

96a 2-Methyl-1-cyclopropanecarbaldehyde

A solution of oxalyl chloride (0.916 ml, 10.5 mmol) in anhydrousdichloromethane (10 mL) was cooled to an internal temperature of below−65° C. under a nitrogen atmosphere. Anhydrous dimethylsulfoxide (1.49mL, 21 mmol) was added dropwise thereto over a period of 15 minutes.After then heating the reaction mixture to −20° C., it was cooled againto below −65° C. A solution of 2-methylcyclopropanemethanol (258 mg, 3mmol) in anhydrous dichloromethane (5 mL) was added dropwise to thereaction mixture over a period of 10 minutes. After stirring for 30minutes under the same conditions, triethylamine (4.18 mL, 30 mmol) wasadded to the mixture, the temperature was gradually raised to roomtemperature. Saturated aqueous solution of ammonium chloride, diethylether and water were added to the reaction mixture and extraction wasperformed with diethyl ether. The separated organic layer was washedtwice with saturated aqueous solution of citric acid, and then withsaturated aqueous solution of sodium hydrogencarbonate and brine in thatorder, after which it was dried over anhydrous sodium sulfate. Thedesiccant was filtered off and the filtrate was concentrated underreduced pressure to give 730 mg of a crude product of the title compoundas a light yellow oil, as a mixture of cis/trans at the position ofcyclopropane ring. This product was directly used without purificationfor the following reaction.

96b1-(2-Methylcyclopropylmethyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

To a mixture of 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine(300 mg, 1 mmol) produced in Example (8b), the crude product of2-methyl-1-cyclopropanecarbaldehyde produced in Example (96a) (365 mg)and tetrahydrofuran (10 mL) were added sodium triacetoxyborohydride (424mg, 2 mmol) and acetic acid (0.057 mL, 1 mmol) in that order, followedby stirring for 15 hours and 30 minutes at room temperature. Ethylacetate, saturated aqueous solution of sodium hydrogencarbonate andwater were added to the reaction mixture and extraction was performedwith ethyl acetate. The separated organic layer was washed with brineand then dried over anhydrous sodium sulfate. The desiccant was filteredoff and the filtrate was concentrated under reduced pressure. Theresultant residue was purified by NH silica gel column chromatography(ethyl acetate/heptane), to give 163 mg of1-(2-methylcyclopropylmethyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazineas a colorless oil, as a mixture of cis/trans at the position ofcyclopropane ring.

¹H-NMR (400 MHz, CDCl₃) δ: 0.24-0.32 (m, 2H), 0.50-0.55 (m, 2H), 0.92(s, 6H), 1.06 (d, J=6.0 Hz, 3H), 1.12 (s, 6H), 1.16-1.48 (m, 6H), 2.18(dd, J=12.4, 7.2 Hz, 1H×0.85), 2.33 (dd, J=12.0, 6.4 Hz, 1H×0.15), 2.50(dd, J=12.4, 6.4 Hz, 1H×0.85), 2.56 (dd, J=12.4, 6.4 Hz, 1H×0.15), 2.67(br, 4H), 2.95 (t, J=4.8 Hz, 4H). 3.58 (tt, J=12.8, 2.8 Hz, 1H),7.05-7.18 (m, 3H), 7.22 (dd, J=7.2, 1.2 Hz, 1H).

This compound was dissolved in dichloromethane, and a 4N solution ofhydrogen chloride in ethyl acetate was added. This solution wasconcentrated under reduced pressure, and diethyl ether was added to theobtained residue to produce a solid, which was filtered. It was thendried under reduced pressure to give 156 mg of the title compound as awhite solid, as a mixture of cis/trans at the position of cyclopropanering.

MS m/e (ESI) 369 (MH⁺).

Example 971-[3-Fluoro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]-4-(tetrahydropyran-4-ylmethyl)piperazinehydrochloride

97a Trifluoromethanesulfonic acid 2-fluoro-6-nitrophenyl ester

A mixture of 2-fluoro-6-nitrophenol (5 g, 31.83 mmol), triethylamine (22mL, 157.84 mmol) and dichloromethane (100 mL) was cooled using anice-methanol bath under a nitrogen atmosphere. To this mixture was addeddropwise trifluoromethanesulfonic anhydride (8 mL, 47.55 mmol) over aperiod of 20 minutes, followed by stirring for 50 minutes under the sameconditions. Saturated aqueous solution of ammonium chloride, ethylacetate and water were added to the reaction mixture and extraction wasperformed with ethyl acetate. The separated organic layer was washedwith saturated aqueous solution of ammonium chloride and brine, and thendried over anhydrous sodium sulfate. The desiccant was filtered off andthe filtrate was concentrated under reduced pressure. The resultantresidue was purified by silica gel column chromatography (ethylacetate/hexane) to give 8.02 g of the title compound as an ochre oil.

¹H-NMR (400 MHz, CDCl₃) δ: 7.52-7.63 (m, 2H), 7.98 (dt, J=8.0, 2.0 Hz,11H).

97b 1-Fluoro-3-nitro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)benzene

To a mixture of trifluoromethanesulfonic acid 2-fluoro-6-nitrophenylester (2.89 g, 10 mmol) produced in Example (97a),4,4,5,5-tetramethyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)[1,3,2]dioxaborolane(3.17 g, 12 mmol) produced in Example (4b), toluene (30 mL) and ethanol(15 mL) were added sodium carbonate (1.6 g, 15.1 mmol), purified water(0.9 mL) and tetrakis(triphenylphosphine)palladium(0) (1.15 g, 1 mmol),followed by stirring for 2 hours at an external temperature of 100° C.under a nitrogen atmosphere. Ethyl acetate and water were added to thereaction mixture and extraction was performed with ethyl acetate. Theseparated organic layer was washed with brine and then dried overanhydrous sodium sulfate. The desiccant was filtered off and thefiltrate was concentrated under reduced pressure. The resultant residuewas purified by silica gel column chromatography (ethyl acetate/hexane)to give 2.25 g of the title compound as a light yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.04 (s, 6H), 1.07 (s, 6H), 1.42 (s, 2H),2.07 (s, 2H), 5.34 (t, J=2.0 Hz, 1H), 7.23-7.29 (m, 1H), 7.33 (ddd,J=8.0, 8.0, 5.2 Hz, 1H), 7.54 (ddd, J=8.0, 2.0, 1.2 Hz, 1H).

97c 3-Fluoro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl amine

To a solution of1-fluoro-3-nitro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)benzene (2.25 g,8.11 mmol) produced in Example (97b) in ethanol (45 mL) were addedammonium chloride (150 mg, 2.8 mmol), water (15 mL) and iron powder (1.6g, 28.65 mmol), followed by stirring for 2 hours at an externaltemperature of 90° C. The reaction mixture was filtered and the filtratewas concentrated under reduced pressure. Ethyl acetate and water wereadded to the obtained residue and extraction was performed with ethylacetate. The separated organic layer was washed with brine and thendried over anhydrous sodium sulfate. The desiccant was filtered off andthe filtrate was concentrated under reduced pressure. The resultantresidue was purified by NH silica gel column chromatography (ethylacetate/heptane) to give 632 mg of the title compound as a light yellowoil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.06 (s, 6H), 1.09 (s, 6H), 1.44 (s, 2H),1.96 (s, 2H), 3.86 (brs, 2H), 5.51 (t, J=1.6 Hz, 1H), 6.43 (ddd, J=8.4,8.0, 1.2 Hz, 1H), 6.46 (ddd, J=8.0, 1.2, 0.8 Hz, 1H), 6.96 (ddd, J=8.4,8.0, 6.4 Hz, 1H).

97d 1-[3-Fluoro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazine

To a solution of3-fluoro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenylamine (623 mg, 2.52mmol) produced in Example (97c) in 1,2-dichlorobenzene (7 mL) was addedbis(2-chloroethyl)amine hydrochloride (560 mg, 3.14 mmol), followed byreflux for 5 hours at an external temperature of 200° C. under anitrogen atmosphere. During the reaction, a nitrogen stream wascirculated into the reactor several times to remove the hydrogenchloride gas. After cooling the reaction mixture to room temperature,ethyl acetate, tetrahydrofuran, methanol, saturated aqueous solution ofsodium carbonate and water were added for partition between oil andwater. The aqueous layer was further extracted with ethyl acetate, andthe combined organic layer was dried over anhydrous sodium sulfate. Thedesiccant was filtered off and the filtrate was concentrated underreduced pressure. The resultant residue was purified by NH silica gelcolumn chromatography (ethyl acetate/heptane) to give 214 mg of thetitle compound as a light brown oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.05 (s, 6H), 1.08 (s, 6H), 1.42 (s, 2H),2.06 (s, 2H), 2.95 (brs, 8H), 5.43 (s, 1H), 6.74 (ddd, J=8.4, 8.0, 0.8Hz, 1H), 6.79 (d, J=8.4 Hz, 1H), 7.12 (ddd, J=8.0, 8.0, 6.4 Hz, 11H).

The 1H of NH could not be identified.

97e1-[3-Fluoro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]-4-(tetrahydropyran-4-ylmethyl)piperazinehydrochloride

To a mixture of1-[3-fluoro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazine (115mg, 0.363 mmol) produced in Example (97d),tetrahydropyran-4-carbaldehyde (62 mg, 0.543 mmol) and tetrahydrofuran(7 mL) were added sodium triacetoxyborohydride (154 mg, 0.726 mmol) andacetic acid (0.021 mL, 0.363 mmol) in that order, followed by stirringfor 1 hour and 30 minutes at room temperature. Ethyl acetate, saturatedaqueous solution of sodium hydrogencarbonate and water were added to thereaction mixture and extraction was performed with ethyl acetate. Theseparated organic layer was washed with brine and then dried overanhydrous sodium sulfate. The desiccant was filtered off and thefiltrate was concentrated under reduced pressure. The resultant residuewas purified by NH silica gel column chromatography (ethylacetate/heptane) to give 108 mg of1-[3-fluoro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]-4-(tetrahydropyran-4-ylmethyl)piperazineas a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.06 (s, 6H), 1.08 (s, 6H), 1.23-1.28 (m,2H), 1.65-1.83 (m, 3H), 1.42 (s, 2H), 2.06 (s, 2H), 2.21 (d, J=7.2 Hz,2H), 2.48 (brs, 4H), 2.99 (brs, 4H), 3.38 (td, J=12, 2.4 Hz, 2H),3.94-4.00 (m, 2H), 5.42 (s, 1H), 6.72 (ddd, J=8.0, 8.0, 0.8 Hz, 1H),6.77 (d, J=8.0 Hz, 1H), 7.10 (ddd, J=8.0, 8.0, 6.4 Hz, 1H).

This compound was dissolved in dichloromethane, and a 4N solution ofhydrogen chloride in ethyl acetate was added. The solution wasconcentrated, and diethyl ether was added to the obtained residue toproduce a solid which was then filtered. The solid was dried underreduced pressure to give 97 mg of the title compound as a white solid.

MS m/e (ESI) 415 (MH⁺).

Example 98(R)-1-Butyl-4-[2-(4,4-diethylcyclohexyl)-4-(3-methoxypyrrolidin-1-yl)phenyl]piperazinehydrochloride

98a(R)-[2-(4,4-Diethylcyclohexyl)-4-(3-methoxypyrrolidin-1-yl)phenyl]piperazine-1′-carboxylicacid t-butyl ester

A mixture of4-[4-bromo-2-(4,4-dimethylcyclohexyl)phenyl]piperazine-1-carboxylic acidt-butyl ester (454 mg, 0.947 mmol) produced in Example (38c), toluene(10 mL), (R)-3-methoxypyrrolidine hydrochloride (196 mg, 1.42 mmol),sodium t-butoxide (380 mg, 3.95 mmol), tri-t-butylphosphoniumtetrafluoroborate (84 mg, 0.29 mmol) and palladium(II) acetate (32 mg,0.14 mmol) was stirred for 5 hours at an external temperature of 90° C.under a nitrogen atmosphere. Insoluble materials of the reaction mixturewere filtered off, and the filtrate was concentrated under reducedpressure. The resultant residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to obtain 193 mg of the titlecompound as a light brown solid.

¹H-NMR (400 MHz, CDCl₃) δ: 0.82 (t, J=7.6 Hz, 6H), 1.16-1.29 (m, 4H),1.47 (s, 9H), 1.48-1.68 (m, 8H), 2.07-2.14 (m, 2H), 2.74 (brs, 4H),2.93-3.03 (m, 1H), 3.13 (br, 4H), 3.28-3.51 (m, 7H), 4.05-4.11 (m, 1H),6.38 (dd, J=8.8, 2.8 Hz, 1H), 6.43 (d, J=2.8 Hz, 1H), 7.01 (d, J=8.8 Hz,1H).

98b(R)-1-[2-(4,4-Diethylcyclohexyl)-4-(3-methoxypyrrolidin-1-yl)phenyl]piperazine

A mixture of(R)-[2-(4,4-dimethylcyclohexyl)-4-(3-methoxypyrrolidin-1-yl)phenyl]piperazine-1-carboxylicacid t-butyl ester (193 mg, 0.386 mmol) produced in Example (98a),trifluoroacetic acid (0.5 mL, 6.49 mmol) and dichloromethane (3 mL) wasstirred for 14 hours and 30 minutes at room temperature. 5N aqueoussolution of sodium hydroxide was added to the reaction mixture cooled inan ice water bath to make the mixture basic. Then, ethyl acetate andwater were added and extraction was performed with ethyl acetate. Theseparated organic layer was washed with brine and then dried overanhydrous sodium sulfate. The desiccant was filtered off and thefiltrate was concentrated under reduced pressure, to give 160 mg of acrude product of the title compound as a light brown oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.80 (t, J=7.6 Hz, 6H), 1.15-1.30 (m, 4H),1.42-1.66 (m, 8H), 2.07-2.14 (m, 2H), 2.79 (t, J=4.8 Hz, 4H), 3.02 (t,J=4.8 Hz, 4H), 2.92-3.00 (m, 1H), 3.28-3.51 (m, 7H), 4.05-4.11 (m, 1H),6.39 (dd, J=8.4, 2.8 Hz, 1H), 6.43 (d, J=2.8 Hz, 1H), 7.07 (d, J=8.4 Hz,1H).

The 1H of NH could not be identified.

98c(R)-1-Butyl-4-[2-(4,4-dimethylcyclohexyl)-4-(3-methoxypyrrolidin-1-yl)phenyl]piperazinehydrochloride

To a mixture of the crude product of(R)-1-[2-(4,4-dimethylcyclohexyl)-4-(3-methoxypyrrolidin-1-yl)phenyl]piperazineproduced in Example (98b) (160 mg), butyraldehyde (0.052 mL, 0.584 mmol)and tetrahydrofuran (7 mL) were added sodium triacetoxyborohydride (164mg, 0.774 mmol) and acetic acid (0.022 mL, 0.384 mmol) in that order,followed by stirring for 1 hour at room temperature. Ethyl acetate andsaturated aqueous solution of sodium hydrogencarbonate were added to thereaction mixture and extraction was performed with ethyl acetate. Theseparated organic layer was washed with brine and then dried overanhydrous sodium sulfate. The desiccant was filtered off and thefiltrate was concentrated under reduced pressure. The resultant residuewas purified by NH silica gel column chromatography (ethylacetate/hexane) to give 170 mg of(R)-1-butyl-4-[2-(4,4-dimethylcyclohexyl)-4-(3-methoxypyrrolidin-1-yl)phenyl]piperazineas a light brown oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.80 (t, J=7.6 Hz, 6H), 0.94 (t, J=7.2 Hz,3H), 1.15-1.40 (m, 6H), 1.45-1.70 (m, 10H), 2.06-2.14 (m, 2H), 2.36-2.43(m, 2H), 2.57 (br, 4H), 2.84 (brs, 4H), 2.90-3.00 (m, 1H), 3.27-3.50 (m,7H), 4.05-4.10 (m, 1H), 6.37 (dd, J=8.8, 2.8 Hz, 1H), 6.42 (d, J=2.8 Hz,1H), 7.08 (d, J=8.8 Hz, 1H).

This compound was dissolved in dichloromethane, and a 4N solution ofhydrogen chloride in ethyl acetate was added. The solution wasconcentrated and diethyl ether was added to the obtained residue toproduce a solid, which was then triturated by sonication. Thesupernatant diethyl ether solution was removed, and the solid residuewas dried under reduced pressure to give 161 mg of the title compound asa light gray solid.

MS m/e (ESI) 456 (MH⁺).

Example 991-Cyclopropylmethyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)-4-thiazol-2-ylphenyl]piperazinedihydrochloride

99a4-[4-Bromo-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine-1-carboxylicacid t-butyl ester

To a mixture of4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine-1-carboxylic acidt-butyl ester (2.93 g, 7.31 mmol) produced in Example (8a), sodiumacetate (6 g, 73.14 mmol) and methanol (50 mL) was added bromine (0.37mL, 7.22 mmol), followed by stirring for 20 minutes at room temperatureunder a nitrogen atmosphere. Saturated aqueous solution of sodiumthiosulfate, ethyl acetate and water were added to the reaction mixtureand extraction was performed with ethyl acetate. The separated organiclayer was washed with brine and then dried over anhydrous sodiumsulfate. The desiccant was filtered off and the filtrate wasconcentrated under reduced pressure. The resultant residue was purifiedby silica gel column chromatography (ethyl acetate/hexane) to give 2.67g of the title compound as colorless crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 0.93 (s, 6H), 1.10 (s, 6H), 1.12-1.45 (m,6H), 1.49 (s, 9H), 2.79 (brs, 4H), 3.48 (br, 4H), 3.54 (tt, J=12.4, 2.8Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 7.25 (dd, J=8.4, 2.4 Hz, 1H), 7.32 (d,J=2.4 Hz, 1H).

99b4-[2-(3,3,5,5-Tetramethylcyclohexyl)-4-thiazol-2-ylphenyl]piperazine-1-carboxylicacid t-butyl ester

To a mixture of4-[4-bromo-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine-1-carboxylicacid t-butyl ester (150 mg, 0.313 mmol) produced in Example (99a),2-(tributyltin)thiazole (0.16 mL), cesium fluoride (107 mg, 0.704 mmol)and dioxane (8 mL) was added tetrakis(triphenylphosphine)palladium(0)(40 mg, 0.035 mmol), followed by stirring for 3 hours at an externaltemperature of 100° C. under a nitrogen atmosphere. Ethyl acetate wasadded to the reaction mixture, insoluble materials were filtered off,and the filtrate was concentrated under reduced pressure. The resultantresidue was purified by silica gel column chromatography (ethylacetate/heptane) to give 115 mg of the title compound as light yellowcrystals.

¹H-NMR (400 MHz, CDCl₃) δ: 0.94 (s, 6H), 1.12 (s, 6H), 1.15-1.46 (m,6H), 1.50 (s, 9H), 2.87 (brs, 4H), 3.56 (tt, J=12.4, 3.2 Hz, 1H), 3.59(br, 4H), 7.09 (d, J=8.4 Hz, 1H), 7.28 (d, J=3.2 Hz, 1H), 7.69 (dd,J=8.4, 2.4 Hz, 1H), 7.84 (d, J=3.2 Hz, 1H), 7.88 (d, J=2.4 Hz, 1H).

99c 1-[2-(3,3,5,5-Tetramethylcyclohexyl)-4-thiazol-2-ylphenyl]piperazine

A mixture of4-[2-(3,3,5,5-tetramethylcyclohexyl)-4-thiazol-2-ylphenyl]piperazine-1-carboxylicacid t-butyl ester (113 mg, 0.234 mmol) produced in Example (99b),trifluoroacetic acid (0.3 mL, 3.89 mmol) and dichloromethane (2 mL) wasstirred for 1 hour and 50 minutes at room temperature. The reactionmixture was cooled in an ice water bath, and then 5N aqueous solution ofsodium hydroxide was added thereto to make the mixture basic. Next,ethyl acetate and water were added and extraction was performed withethyl acetate. The separated organic layer was washed with water andbrine and then dried over anhydrous sodium sulfate. The desiccant wasfiltered off and the filtrate was concentrated under reduced pressure togive 91 mg of a crude product of the title compound as a light yellowsolid.

¹H-NMR (400 MHz, CDCl₃) δ: 0.94 (s, 6H), 1.13 (s, 6H), 1.16-1.50 (m,6H), 2.90 (t, J=4.8 Hz, 4H), 3.05 (t, J=4.8 Hz, 4H), 3.56 (tt, J=12.8,2.8 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 7.26 (d, J=3.2 Hz, 1H), 7.68 (dd,J=8.4, 2.4 Hz, 1H), 7.82 (d, J=3.2 Hz, 1H), 7.86 (d, J=2.4 Hz, 1H).

The 1H of NH could not be identified.

99d1-Cyclopropylmethyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)-4-thiazol-2-ylphenyl]piperazinedihydrochloride

To a mixture of1-[2-(3,3,5,5-tetramethylcyclohexyl)-4-thiazol-2-ylphenyl]piperazine (15mg, 0.039 mmol) produced in Example (99c), cyclopropanecarbaldehyde(0.006 mL, 0.080 mmol) and tetrahydrofuran (2 mL) were added sodiumtriacetoxyborohydride (21 mg, 0.099 mmol) and acetic acid (0.003 mL,0.052 mmol) in that order, followed by stirring for 1 hour and 40minutes at room temperature. Ethyl acetate, saturated aqueous solutionof sodium hydrogencarbonate and water were added to the reaction mixtureand extraction was performed with ethyl acetate. The separated organiclayer was concentrated by blowing nitrogen. The resultant residue waspurified by NH silica gel column chromatography (ethyl acetate/hexane)to give1-cyclopropylmethyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)-4-thiazol-2-ylphenyl]piperazine.This compound was dissolved in dichloromethane, and a 4N solution ofhydrogen chloride in ethyl acetate was added. The solution wasconcentrated by blowing nitrogen, and then diethyl ether was added tothe obtained residue to produce a solid, which was then triturated bysonication. The supernatant diethyl ether solution was removed, and theobtained solid residue was dried by blowing nitrogen, to give 16 mg ofthe title compound as a light yellow solid.

MS m/e (ESI) 438 (MH⁺).

Example 1001-Cyclopropylmethyl-4-[4-pyridin-2-yl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinedihydrochloride

100a4-[4-Pyridin-2-yl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine-1-carboxylicacid t-butyl ester

To a mixture of4-[4-bromo-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine-1-carboxylicacid t-butyl ester (100 mg, 0.209 mmol) produced in Example (99a),2-(tributyltin)pyridine (0.08 mL, 0.25 mmol), cesium fluoride (68 mg,0.448 mmol) and dioxane (15 mL) was addedtetrakis(triphenylphosphine)palladium(0) (25 mg, 0.022 mmol), followedby stirring for 3 hours at an external temperature of 90° C. under anitrogen atmosphere. Ethyl acetate was added to the reaction mixture,insoluble materials were filtered off, and the filtrate was concentratedunder reduced pressure. The resultant residue was purified by silica gelcolumn chromatography (ethyl acetate/hexane) to give 43 mg of the titlecompound as light yellow crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 0.94 (s, 6H), 1.13 (s, 6H), 1.16-1.49 (m,6H), 1.50 (s, 9H), 2.88 (brs, 4H), 3.59 (br, 4H), 3.61 (tt, J=12.8, 3.2Hz, 1H), 7.15 (d, J=8.4 Hz, 1H), 7.19 (ddd, J=7.2, 4.8, 2.0 Hz, 1H),7.68-7.76 (m, 3H), 7.89 (d, J=2.4 Hz, 1H), 8.68 (ddd, J=4.8, 1.6, 0.8Hz, 1H).

100b1-[4-Pyridin-2-yl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine

A mixture of4-[4-pyridin-2-yl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine-1-carboxylicacid t-butyl ester (42 mg, 0.088 mmol) produced in Example (100a),trifluoroacetic acid (0.1 mL, 1.30 mmol) and dichloromethane (1 mL) wasstirred for 17 hours and 50 minutes at room temperature. The reactionmixture was cooled in an ice water bath, and then 5N aqueous solution ofsodium hydroxide was added to make the mixture basic. Then, ethylacetate and water were added and extraction was performed with ethylacetate. The separated organic layer was washed with brine and thendried over anhydrous sodium sulfate. The desiccant was filtered off andthe filtrate was concentrated under reduced pressure to give 30 mg of acrude product of the title compound as a light yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.94 (s, 6H), 1.14 (s, 6H), 1.17-1.52 (m,6H), 2.90 (t, J=4.4 Hz, 4H), 3.05 (t, J=4.8 Hz, 4H), 3.61 (tt, J=12.8,3.2 Hz, 1H), 7.14-7.18 (m, 2H), 7.66-7.75 (m, 3H), 7.87 (d, J=2.0 Hz,1H), 8.66 (ddd, J=5.2, 1.6, 0.8 Hz, 1H).

The 1H of NH could not be identified.

100c1-Cyclopropylmethyl-4-[4-pyridin-2-yl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinedihydrochloride

To a mixture of1-[4-pyridin-2-yl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (10mg, 0.026 mmol) produced in Example (100b), cyclopropanecarbaldehyde(0.004 mL, 0.054 mmol) and tetrahydrofuran (2 mL) were added sodiumtriacetoxyborohydride (14 mg, 0.066 mmol) and acetic acid (0.002 mL,0.035 mmol) in that order, followed by stirring for 40 minutes at roomtemperature. Ethyl acetate, saturated aqueous sodium hydrogencarbonateand water were added to the reaction mixture and extraction wasperformed with ethyl acetate. The separated organic layer wasconcentrated by blowing nitrogen. The resultant residue was purified byNH silica gel column chromatography (ethyl acetate/hexane) to give1-cyclopropylmethyl-4-[4-pyridin-2-yl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine.This compound was dissolved in dichloromethane, and a 4N solution ofhydrogen chloride in ethyl acetate was added. The solution wasconcentrated by blowing nitrogen gas, and diethyl ether was added to theobtained residue to produce a solid. After triturating the solid bysonication, the supernatant diethyl ether solution was removed. Thesolid residue was dried by blowing nitrogen, to give 3 mg of the titlecompound as a light yellow solid.

MS m/e (ESI) 432 (MH⁺).

Example 1011-Butyl-4-[2-(4-t-butylcyclohexyl)-5-(1H-tetrazol-5-yl)phenyl]piperazinehydrochloride

101a [4-(4-t-Butylcyclohexyl)-3-(4-butylpiperazine-1-yl)phenyl]methanol

Lithium aluminum hydride (29 mg, 0.764 mmol) was suspended in anhydroustetrahydrofuran (5 mL). To the suspension was added a solution of4-(4-t-butylcyclohexyl)-3-(4-butylpiperazine-1-yl)benzoic acid methylester (308 mg, 0.743 mmol) in anhydrous tetrahydrofuran (5 mL) at roomtemperature under a nitrogen atmosphere, followed by stirring for 55minutes. Sodium fluoride (262 mg) was added to the reaction mixture, andwater (0.11 mL) was gradually added while blowing nitrogen. Afterstirring for 1 hour and 35 minutes, insoluble materials were filteredoff and the filtrate was concentrated under reduced pressure. Theobtained residue was dissolved in ethyl acetate, and anhydrous sodiumsulfate was added for drying. The desiccant was filtered off and thefiltrate was concentrated under reduced pressure to give 295 mg of acrude product of the title compound as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.88 (s, 9H×0.6), 0.90 (s, 9H×0.4), 0.94 (t,J=7.2 Hz, 3H×0.6), 0.95 (t, J=7.2 Hz, 3H×0.4), 1.08-1.98 (m, 13H),2.38-2.44 (m, 2H), 2.59 (brs, 4H), 2.89 (t, J=4.8 Hz, 4H×0.6), 2.90 (t,J=4.8 Hz, 4H×0.4), 2.97 (tt, J=12.4, 2.4 Hz, 1H×0.4), 3.37 (tt, J=5.2,5.2 Hz, 1H×0.6), 4.63 (s, 2H), 7.04-7.08 (m, 1H), 7.11 (d, J=1.6 Hz,1H×0.4), 7.17 (d, J=1.6 Hz, 1H×0.6), 7.20 (d, J=8.0 Hz, 1H×0.4), 7.40(d, J=8.0 Hz, 1H×0.6).

The 1H of OH could not be identified.

101b 4-(4-t-Butylcyclohexyl)-3-(4-butylpiperazine-1-yl)benzaldehyde

A mixture of the crude product of[4-(4-t-butylcyclohexyl)-3-(4-butylpiperazine-1-yl)phenyl]methanolproduced in Example (101a) (294 mg), manganese(IV) oxide (1.3 g, 14.95mmol) and chloroform (15 mL) was refluxed for 40 minutes. The reactionmixture was filtered and insoluble materials were filtered off. Thefiltrate was concentrated under reduced pressure to give 249 mg of acrude product of the title compound as an ochre oil. This product wasdirectly used without purification for the following reaction.

101c 4-(4-t-Butylcyclohexyl)-3-(4-butylpiperazine-1-yl)benzaldehydeoxime

To a mixture of the crude product of4-(4-t-butylcyclohexyl)-3-(4-butylpiperazine-1-yl)benzaldehyde producedin Example (101b) (247 mg), hydroxylammonium chloride (134 mg, 1.93mmol) and ethanol (10 mL) were added sodium acetate (193 mg, 2.35 mmol)and water (1.5 mL), followed by stirring for 2 hours at roomtemperature. The reaction mixture was poured into ice water, and thenethyl acetate and saturated aqueous solution of ammonium chloride wereadded and extraction was performed with ethyl acetate. The separatedorganic layer was washed with brine and then dried over anhydrous sodiumsulfate. The desiccant was filtered off, and the filtrate wasconcentrated under reduced pressure to give 271 mg of a crude product ofthe title compound as a light yellow solid. This product was directlyused without purification for the following reaction.

101d 4-(4-t-Butylcyclohexyl)-3-(4-butylpiperazine-1-yl)benzonitrile

A mixture of the crude product of4-(4-t-butylcyclohexyl)-3-(4-butylpiperazine-1-yl)benzaldehydeoximeproduced in Example (101c) (269 mg), benzenesulfonyl chloride (0.11 mL,0.862 mmol), pyridine (0.11 ml, 1.36 mmol) and tetrahydrofuran (15 mL)was refluxed for 4 hours and 30 minutes. After then distilling offtetrahydrofuran partially in the reaction mixture under reducedpressure, chloroform was added and the mixture was further refluxed for1 hour. The reaction mixture was concentrated under reduced pressure,the obtained residue was poured into ice water, and then ethyl acetateand saturated aqueous solution of ammonium chloride were added andextraction was performed with ethyl acetate. The separated organic layerwas washed twice with saturated aqueous ammonium chloride and once withbrine, and then dried over anhydrous sodium sulfate. The desiccant wasfiltered off, and the filtrate was concentrated under reduced pressureto give a residue, which was purified by NH silica gel columnchromatography (ethyl acetate/hexane, followed by ethylacetate/methanol), to give 192 mg of the title compound as an ochre oil.

101e1-Butyl-4-[2-(4-t-butylcyclohexyl)-5-(1H-tetrazol-5-yl)phenyl]piperazinehydrochloride

A mixture of4-(4-t-butylcyclohexyl)-3-(4-butylpiperazine-1-yl)benzonitrile (146 mg,0.383 mmol) produced in Example (101d), trimethyltin azide (160 mg,0.777 mmol) and toluene (10 mL) was stirred for 14 hours and 20 minutesat an external temperature of about 130° C. The reaction mixture wasconcentrated under reduced pressure, and then methanol (6 mL) and 1Nhydrochloric acid (6 mL) were added to the residue and the mixture wasstirred for 2 hours and 10 minutes at room temperature. The reactionmixture was cooled in an ice water bath, and then 2N aqueous solution ofsodium hydroxide was added to make the mixture basic, after which themixture was neutralized again with saturated aqueous solution ofammonium chloride. Ethyl acetate, tetrahydrofuran and water were addedthereto and extraction was performed with ethyl acetate. The separatedorganic layer was washed with brine and then dried over anhydrous sodiumsulfate. The desiccant was filtered off and the filtrate wasconcentrated under reduced pressure. The resultant residue was dissolvedin dichloromethane, and a 4N solution of hydrogen chloride in ethylacetate was added. The mixture was then concentrated under reducedpressure, and diethyl ether was added to the obtained residue forcrystallization. The crystals were filtered and dried under reducedpressure to give 133 mg of the title compound as colorless crystals.

MS m/e (ESI) 425 (MH⁺).

Example 102 1-Butyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-1,2,3,6-tetrahydropyridine hydrochloride

102a 2-(3,3,5,5-Tetramethylcyclohex-1-enyl)phenol

To a mixture of 2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenol(3.5 g, 15.9 mmol), trifluoromethanesulfonic acid3,3,5,5-tetramethylcyclohex-1-enyl ester (5 g, 17.4 mmol) produced inExample (4a) and 1,2-dimethoxyethane (20 mL) were addedtetrakis(triphenylphosphine)palladium(0) (0.92 g, 0.79 mmol) and 2Naqueous solution of sodium carbonate (23.9 mL, 47.7 mmol), followed bystirring for 1 hour at an external temperature of 90° C. under anitrogen atmosphere. Brine was added to the reaction mixture andextraction was performed with ethyl acetate. The organic layer was driedover anhydrous magnesium sulfate and then the solvent was distilled offunder reduced pressure and the obtained residue was purified by silicagel column chromatography (ethyl acetate/heptane) to give 3.7 g of thetitle compound as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.06 (s, 6H), 1.11 (s, 6H), 1.45 (s, 2H),2.04 (d, J=1.6 Hz, 2H), 5.59 (s, 1H), 5.61 (t, J=1.6 Hz, 1H), 6.87 (td,J=7.6, 1.2 Hz, 1H), 6.90 (dd, J=7.6, 1.2 Hz, 1H), 7.03 (dd, J=7.6, 1.2Hz, 1H), 7.12 (td, J=7.6, 1.2 Hz, 1H).

102b 2-(3.3, 5,5-Tetramethylcyclohexyl)phenol

To a solution of 2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenol (1.7 g,7.4 mmol) produced in Example (102a) in methanol (30 mL) was added 10%palladium on carbon (0.5 g, wet), followed by stirring for 27 hours atroom temperature and atmospheric pressure under a hydrogen atmosphere.The reaction mixture was filtered through Celite, and the filtrate wasconcentrated under reduced pressure to give 1.7 g of a crude product ofthe title compound as a light yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.94 (s, 6H), 1.12 (s, 6H), 1.14-1.35 (m,6H), 3.22 (tt, J=12.8, 2.8 Hz, 1H), 4.67 (s, 1H), 6.74 (dd, J=7.6, 1.2Hz, 1H), 6.89 (td, J=7.6, 1.2 Hz, 1H), 7.05 (td, J=7.6, 1.2 Hz, 1H),7.17 (dd, J=7.6, 1.2 Hz, 1H).

102c Trifluoromethanesulfonic acid2-(3,3,5,5-tetramethylcyclohexyl)phenyl ester

To a solution of 2-(3,3,5,5-tetramethylcyclohexyl)phenol (530 mg, 2.28mmol) produced in Example (102b) in dichloromethane (20 mL) were addedtriethylamine (1.3 mL, 4.09 mmol) and trifluoromethanesulfonic anhydride(0.56 mL, 3.33 mmol) in that order while cooling in an ice bath,followed by stirring for 14 hours while heating to room temperature.Brine was added to the reaction mixture and extraction was performedwith diethyl ether. The organic layer was dried over anhydrous magnesiumsulfate and then filtered, and the filtrate was concentrated underreduced pressure. The resultant residue was purified by silica gelcolumn chromatography (ethyl acetate/heptane) to give 0.83 g of thetitle compound as a light yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.94 (s, 6H), 1.12 (s, 6H), 1.14-1.38 (m,6H), 3.31 (tt, J=12.8, 2.8 Hz, 1H), 7.22-7.42 (m, 4H).

102d4-[2-(3,3,5,5-Tetramethylcyclohexyl)phenyl]-3,6-dihydro-2H-pyridine-1-carboxylicacid t-butyl ester

To a mixture of trifluoromethanesulfonic acid2-(3,3,5,5-tetramethylcyclohexyl)phenyl ester (830 mg, 2.55 mmol)produced in Example (102c),4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid t-butyl ester (631 mg, 2.04 mmol) (Paul R. Eastwood, TetrahedronLett., 2000, 41, 3705) and 1,2-dimethoxyethane (20 mL) were addedtetrakis(triphenylphosphine)palladium (147 mg, 0.13 mmol) and 2N aqueoussolution of sodium carbonate (3.8 mL, 7.6 mmol), followed by stirringfor 8 hours at an external temperature of 90° C. under a nitrogenatmosphere. Brine was added to the reaction mixture and extraction wasperformed with ethyl acetate. The organic layer was dried over anhydrousmagnesium sulfate and the filtrate was concentrated under reducedpressure. The resultant residue was purified by silica gel columnchromatography (ethyl acetate/heptane) to give 570 mg of the titlecompound as a light yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.03 (s, 6H), 1.12 (s, 6H), 1.16-1.48 (m,6H), 1.49 (s, 9H), 2.32 (bs, 2H), 3.22 (tt, J=12.8, 2.8 Hz, 1H), 3.64(bs, 2H), 4.02 (bs, 2H), 5.52 (bs, 1H), 6.74 (dd, J=7.6, 1.2 Hz, 1H),6.89 (td, J=7.6, 1.2 Hz, 1H), 7.05 (td, J=7.6, 1.2 Hz, 1H), 7.17 (dd,J=7.6, 1.2 Hz, 1H).

102e4-[2-(3,3,5,5-Tetramethylcyclohexyl)phenyl]-1,2,3,6-tetrahydropyridine

To a solution of4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-3,6-dihydro-2H-pyridine-1-carboxylicacid t-butyl ester (570 mg, 1.43 mmol) produced in Example (102d) indichloromethane (5 mL) was added trifluoroacetic acid (5 mL), followedby stirring for 30 minutes at room temperature. The reaction mixture wasconcentrated under reduced pressure, saturated aqueous solution ofsodium hydrogencarbonate was added to the obtained residue, andextraction was performed with ethyl acetate. The organic layer was driedover anhydrous magnesium sulfate and then the filtrate was concentratedunder reduced pressure. The resultant residue was purified by silica gelcolumn chromatography (ethyl acetate/heptane) to give 430 mg of thetitle compound as a light yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.92 (s, 6H), 1.05 (s, 6H), 1.10-1.52 (m,6H), 2.35 (bs, 2H), 3.07 (tt, J=12.8, 2.8 Hz, 1H), 3.21 (t, J=5.6 Hz,2H), 3.57-3.62 (m, 2H), 5.56-5.61 (m, 1H), 7.00 (dd, J=7.6, 1.2 Hz, 1H),7.12 (td, 7.6, 1.2 Hz, 1H), 7.22-7.27 (m, 1H), 7.36 (td, J=7.6, 1.2 Hz,1H).

The 1H of NH could not be identified.

MS m/e (ESI) 298 (MH⁺).

102f1-Butyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-1,2,3,6-tetrahydropyridinehydrochloride

To a solution of4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-1,2,3,6-tetrahydropyridine(130 mg, 0.44 mmol) produced in Example (102e) in tetrahydrofuran (2 mL)were added butyraldehyde (37.8 mg, 0.52 mmol), sodiumtriacetoxyborohydride (139 mg, 0.66 mmol) and acetic acid (52.5 mg, 0.87mmol), followed by stirring for 13 hours at room temperature. Saturatedaqueous solution of sodium hydrogencarbonate was added to the reactionmixture and extraction was performed with ethyl acetate. The organiclayer was dried over anhydrous magnesium sulfate and then the filtratewas concentrated under reduced pressure. The resultant residue waspurified by NH silica gel column chromatography (ethyl acetate/heptane)to give 70 mg of1-butyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-1,2,3,6-tetrahydropyridineas a light yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.91 (s, 6H), 0.94 (t, J=7.2 Hz, 3H), 1.05(s, 6H), 1.12-1.46 (m, 10H), 2.33-2.40 (m, 2H), 2.46 (t, J=7.2 Hz, 2H),2.69 (t, J=5.6 Hz, 2H), 3.06-3.12 (m, 3H), 5.49-5.54 (m, 1H), 7.17-7.32(m, 4H).

The obtained compound was dissolved in ethyl acetate, and then a 4Nsolution of hydrogen chloride in ethyl acetate was added and the mixturewas stirred for 30 minutes at room temperature. The reaction mixture wasconcentrated under reduced pressure and hexane was added to the obtainedresidue to produce a solid, which was then triturated by sonication. Thesolid was filtered and dried under reduced pressure to give 68 mg of thetitle compound as a light yellow solid.

MS m/e (ESI) 354 (MH⁺).

Example 1031-Butyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperidinehydrochloride

To a solution of1-butyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-1,2,3,6-tetrahydropyridinehydrochloride (48 mg, 0.12 mmol) produced in Example (102f) in methanol(3 mL) was added 10% palladium on carbon (100 mg, wet), followed bystirring for 4 hours at room temperature and atmospheric pressure undera hydrogen atmosphere. The reaction mixture was filtered through Celite,and the filtrate was concentrated under reduced pressure. Ether andhexane were added to the obtained residue to produce a solid, which wasthen triturated by sonication. The solid was filtered and dried underreduced pressure to give 9 mg of the title compound as a light yellowsolid.

¹H-NMR (400 MHz, CD₃OD) δ: 0.97 (s, 6H), 1.03 (t, J=7.2 Hz, 3H), 1.19(s, 6H), 1.30-1.52 (m, 8H), 1.74-1.84 (m, 2H), 1.96-2.17 (m, 4H),3.02-3.30 (m, 6H), 3.68-3.77 (m, 2H), 7.14-7.30 (m, 4H). MS m/e (ESI)356 (MH⁺).

Example 1044-[4-Methyl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-1-propyl-1,2,3,6-tetrahydropyridinehydrochloride

104a 1-Methoxy-4-methyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)benzene

To a mixture of 2-methoxy-5-methylphenylboronic acid (1 g, 6.02 mmol),trifluoromethanesulfonic acid 3,3,5,5-tetramethylcyclohex-1-enyl ester(1.9 g, 6.62 mmol) produced in Example (4a) and 1,2-dimethoxyethane (30mL) were added tetrakis(triphenylphosphine)palladium(0) (0.35 g, 0.30mmol) and 2N aqueous solution of sodium carbonate (9.0 mL, 18.0 mmol),followed by stirring for 3 hours at an external temperature of 90° C.under a nitrogen atmosphere. Brine was added to the reaction mixture andextraction was performed with ethyl acetate. The organic layer was driedover anhydrous magnesium sulfate and filtrated, the resultant filtratewas concentrated under reduced pressure to give a residue, which waspurified by silica gel column chromatography (ethyl acetate/heptane) togive 1.0 g of the title compound as a light yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.01 (s, 6H), 1.07 (s, 6H), 1.39 (s, 2H),2.07 (d, J=1.6 Hz, 2H), 2.28 (s, 3H), 3.75 (s, 3H), 5.42 (s, 1H), 6.73(d, J=8.4 Hz, 1H), 6.91 (d, J=2.0 Hz, 1H), 6.97 (dd, J=8.4, 2.0 Hz, 1H).

104b 1-Methoxy-4-methyl-2-(3,3,5,5-tetramethylcyclohexyl)benzene

To a solution of1-methoxy-4-methyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)benzene (1.0 g,3.87 mmol) produced in Example (104a) in methanol (30 mL) was added 10%palladium on carbon (0.6 g, wet), followed by stirring for 12 hours atroom temperature and atmospheric pressure under a hydrogen atmosphere.The reaction mixture was filtered through Celite, and the filtrate wasconcentrated under reduced pressure to give 1.0 g of a crude product ofthe title compound as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.92 (s, 6H), 1.05 (s, 6H), 1.10-1.52 (m,6H), 2.80 (s, 3H), 3.33 (tt, J=12.8, 2.8 Hz, 1H), 3.79 (s, 3H), 6.75 (d,J=8.4 Hz, 1H), 6.94 (d, J=2.0 Hz, 1H), 6.99 (dd, J=8.4, 2.0 Hz, 1H).

104c 4-Methyl-2-(3,3,5,5-tetramethylcyclohexyl)phenol

To a solution of1-methoxy-4-methyl-2-(3,3,5,5-tetramethylcyclohexyl)benzene (1.0 g, 3.84mmol) produced in Example (104b) in acetic acid (5 mL) was added 48%hydrobromic acid (10 mL, 59.3 mmol), followed by reflux for 12 hours.Saturated aqueous solution of sodium hydrogencarbonate was added to thecooled reaction mixture, and extraction was performed with ethylacetate. The organic layer was dried over anhydrous magnesium sulfateand the filtrate was concentrated under reduced pressure to give aresidue, which was purified by silica gel column chromatography (ethylacetate/heptane) to give 450 mg of the title compound as a light yellowoil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.94 (s, 6H), 1.12 (s, 6H), 1.16-1.60 (m,6H), 2.26 (s, 3H), 3.18 (tt, J=12.8, 2.8 Hz, 1H), 4.47 (s, 1H), 6.64 (d,J=8.4 Hz, 1H), 6.84 (dd, J=8.4, 2.0 Hz, 1H), 6.96 (d, J=2.0 Hz, 1H).

104d Trifluoromethanesulfonic acid4-methyl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl ester

To a solution of 4-methyl-2-(3,3,5,5-tetramethylcyclohexyl)phenol (0.45g, 1.83 mmol) produced in Example (104c) in dichloromethane (30 ml)cooled in an ice bath were added triethylamine (1.0 mL, 7.32 mmol) andtrifluoromethanesulfonic anhydride (0.46 mL, 2.75 mmol) in that order,followed by stirring for 2 hours at an external temperature of 0° C.Brine was added to the reaction mixture and extraction was performedwith ethyl acetate. The organic layer was dried over anhydrous magnesiumsulfate, and the filtrate was concentrated under reduced pressure togive a residue, which was purified by silica gel column chromatography(ethyl acetate/heptane) to give 0.43 g of the title compound as a lightyellow oil.

¹H-NMR (400 MHz, CDCl3) δ: 0.94 (s, 6H), 1.11 (s, 6H), 1.08-1.54 (m,6H), 2.35 (s, 3H), 3.26 (tt, J=12.8, 2.8 Hz, 1H), 7.02 (dd, J=8.4, 2.0Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 7.14 (d, J=2.0 Hz, 1H).

104e4-[4-Methyl-2-(3,3,5,5-tetramethylcyclohexl)phenyl]-3,6-dihydro-2H-pyridine-1-carboxylicacid t-butyl ester

To a mixture of trifluoromethanesulfonic acid4-methyl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl ester (430 mg, 1.14mmol) produced in Example (104d),4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid t-butyl ester (421 mg, 1.36 mmol) (Paul R. Eastwood, TetrahedronLett., 2000, 41, 3705) and 1,2-dimethoxyethane (20 mL) were addedtetrakis(triphenylphosphine)palladium(0) (65 mg, 0.06 mmol) and 2Naqueous solution of sodium carbonate (1.72 mL, 3.41 mmol), followed bystirring for 8 hours at an external temperature of 90° C. under anitrogen atmosphere. Brine was added to the reaction mixture andextraction was performed with ethyl acetate. The organic layer was driedover anhydrous magnesium sulfate and the filtrate was concentrated togive a residue, which was purified by silica gel column chromatography(ethyl acetate/heptane) to give 297 mg of the title compound as a lightyellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.91 (s, 6H), 1.02 (s, 6H), 1.09-1.44 (m,6H), 1.48 (s, 9H), 2.30 (bs, 2H), 2.33 (s, 3H), 3.04 (tt, J=12.8, 2.8Hz, 1H), 3.63 (bs, 2H), 4.01 (bs, 2H), 5.49 (bs, 1H), 6.94 (s, 2H), 7.04(s, 1H).

104f4-[4-Methyl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-1,2,3,6-tetrahydropyridine

To a solution of4-[4-methyl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-3,6-dihydro-2H-pyridine-1-carboxylicacid t-butyl ester (297 mg, 0.72 mmol) produced in Example (104e) indichloromethane (3 mL) was added trifluoroacetic acid (3 mL), followedby stirring for 30 minutes at room temperature. The reaction mixture wasconcentrated under reduced pressure, and then saturated aqueous solutionof sodium hydrogencarbonate was added to the residue and extraction wasperformed with ethyl acetate. The organic layer was dried with adesiccant and then filtered. The filtrate was concentrated under reducedpressure to give 280 mg of a crude product of the title compound as alight yellow oil.

MS m/e (ESI) 312 (MH⁺).

104g4-[4-Methyl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-1-propyl-1,2,3,6-tetrahydropyridinehydrochloride

To a solution of4-[4-methyl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-1,2,3,6-tetrahydropyridine(70 mg, 0.23 mmol) produced in Example (104f) in tetrahydrofuran (2 mL)were added propionaldehyde (15.7 mg, 0.27 mmol), sodiumtriacetoxyborohydride (72 mg, 0.34 mmol) and acetic acid (27 mg, 0.45mmol), followed by stirring for 12 hours at room temperature. Saturatedaqueous solution of sodium hydrogencarbonate was added to the reactionmixture and extraction was performed with ethyl acetate. The organiclayer was dried over anhydrous magnesium sulfate and the filtrate wasconcentrated to give a residue, which was purified by NH silica gelcolumn chromatography (ethyl acetate/heptane) to give 63 mg of4-[4-methyl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-1-propyl-1,2,3,6-tetrahydropyridineas a light yellow oil.

MS m/e (ESI) 354 (MH⁺).

The obtained compound was dissolved in ethyl acetate, and a 4N solutionof hydrogen chloride in ethyl acetate was added and the mixture wasstirred for 30 minutes at room temperature. The solution wasconcentrated under reduced pressure, and then hexane was added to theresidue to produce a solid which was triturated by sonication. The solidwas filtered and dried under reduced pressure to give 60 mg of the titlecompound as a light yellow solid.

¹H-NMR (400 MHz, CD₃OD) δ: 0.95 (s, 6H), 1.06 (t, J=7.2 Hz, 3H), 1.11(s, 6H), 1.16-1.46 (m, 8H), 1.77-1.89 (m, 2H), 2.31 (s, 3H), 2.56-2.68(m, 2H), 3.01 (tt, J=12.8, 2.8 Hz, 1H), 3.12-3.24 (m, 2H), 3.76-3.92 (m,2H), 5.58 (bs, 1H), 6.96 (s, 2H), 7.11 (s, 1H). MS m/e (ESI) 354 (MH⁺).

Example 1054-[4-Methyl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-1-propylpiperidinehydrochloride

To a solution of4-[4-methyl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-1-propyl-1,2,3,6-tetrahydropyridinehydrochloride (50 mg, 0.13 mmol) produced in Example (104g) in methanol(10 mL) was added 10% palladium on carbon (50 mg, wet), followed bystirring for 2 hours at atmospheric pressure and room temperature undera hydrogen atmosphere. The reaction mixture was filtered through Celite,and the obtained filtrate was concentrated under reduced pressure.Hexane was added to the residue to produce a solid, which was thentriturated by sonication. The solid was filtered and dried under reducedpressure to give 16 mg of the title compound as a light yellow solid.

¹H-NMR (400 MHz, CD₃OD) δ: 0.97 (s, 6H), 1.05 (t, 3H), 1.18 (s, 6H),1.18-1.46 (m, 6H), 1.74-1.86 (m, 2H), 1.95-2.08 (m, 4H), 2.29 (s, 3H),3.00-3.34 (m, 6H), 3.62-3.72 (m, 2H), 6.99 (dd, J=8.4, 2.0 Hz, 1H), 7.08(d, J=2.0 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H). MS m/e (ESI) 356 (MH⁺).

Example 1061-Butyl-4-[5-fluoro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperidinehydrochloride

106a 4-(5-Fluoro-2-methoxyphenyl)-3,6-dihydro-2H-pyridine-1-carboxylicacid t-butyl ester

To a mixture of 5-fluoro-2-methoxyphenylboronic acid (1 g, 5.88 mmol),4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acidt-butyl ester (4.22 g, 7.64 mmol) (David J. Wustrow, Lawrence D. Wise,Synthesis, 1991, 993) and 1,2-dimethoxyethane (30 mL) were addedtetrakis(triphenylphosphine)palladium(0) (0.34 g, 0.29 mmol) and 2Naqueous solution of sodium carbonate (8.82 mL, 17.6 mmol), followed bystirring for 2 hours at an external temperature of 90° C. under anitrogen atmosphere. Brine was added to the reaction mixture andextraction was performed with ethyl acetate. The organic layer was driedover anhydrous magnesium sulfate and the filtrate was concentrated togive a residue, which was purified by silica gel column chromatography(ethyl acetate/heptane) to give 2.3 g of the title compound as a yellowoil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.49 (s, 9H), 2.47 (bs, 2H), 3.58 (t, J=5.6Hz, 2H), 3.78 (s, 3H), 4.01-4.06 (m, 2H), 5.78 (bs, 1H), 6.77 (dd,J=8.4, 4.4 Hz, 1H), 6.88 (td, J=9.2, 3.2 Hz, 1H), 6.91 (dd, J=8.8, 3.2Hz, 1H).

106b 4-(5-Fluoro-2-methoxyphenyl)piperidine-1-carboxylic acid t-butylester

To a solution of4-(5-fluoro-2-methoxyphenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acidt-butyl ester (2.0 g, 6.5 mmol) produced in Example (106a) in methanol(30 mL) was added 10% palladium on carbon (0.99 g, wet), the mixture wasstirred for 17 hours at atmospheric pressure and room temperature undera hydrogen atmosphere. The reaction mixture was filtered through Celite,and the obtained filtrate was concentrated under reduced pressure togive 2.0 g of the title compound as a light yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.48 (s, 9H), 1.50-1.82 (m, 4H), 3.06 (tt,J=12.8, 2.8 Hz, 1H), 3.55-3.62 (m, 2H), 3.78 (s, 3H), 4.01-4.06 (m, 2H),6.77 (dd, J=8.8, 4.8 Hz, 1H), 6.81-6.93 (m, 2H).

106c 4-Fluoro-2-piperidin-4-ylphenol

To a solution of 4-(5-fluoro-2-methoxyphenyl)piperidine-1-carboxylicacid t-butyl ester (2.0 g, 6.46 mmol) produced in Example (106b) indichloromethane (50 mL) was added boron tribromide (1M solution intetrahydrofuran, 19.4 mL, 19.4 mmol), followed by stirring for 4 hoursat an external temperature of 60° C. Saturated aqueous solution ofsodium hydrogencarbonate was added to the reaction mixture andextraction was performed with dichloromethane. The organic layer wasdried over anhydrous magnesium sulfate, and the filtrate wasconcentrated under reduced pressure to give 840 mg of a crude product ofthe title compound as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.80-2.00 (m, 4H), 2.80-3.16 (m, 4H),3.44-3.54 (m, 2H), 6.59 (dd, J=9.2, 3.2 Hz, 1H), 6.64 (dd, J=8.8, 4.4Hz, 1H), 6.75 (td, J=8.0, 3.2 Hz, 1H). 1H could not be identified.

MS m/e (ESI) 195 (MH⁺).

106d 4-(5-Fluoro-2-hydroxyphenyl)piperidine-1-carboxylic acid t-butylester

To a solution of 4-fluoro-2-piperidin-4-ylphenol (840 mg, 4.30 mmol)produced in Example (106c) in tetrahydrofuran (20 mL) were addedtriethylamine (0.78 mL, 5.59 mmol) and di-t-butyl dicarbonate (1.03 g,4.73 mmol) in that order, followed by stirring for 1 hour and 30 minutesat room temperature. Brine was added to the reaction mixture andextraction was performed with ethyl acetate. The organic layer was driedover anhydrous magnesium sulfate and then the filtrate was concentratedunder reduced pressure to give a residue, which was purified by silicagel column chromatography (ethyl acetate/heptane) to give 360 mg of thetitle compound as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.48 (s, 9H), 1.50-1.62 (m, 2H), 1.77-1.85(m, 2H), 2.70-2.90 (m, 2H), 3.00 (tt, J=12.8, 2.8 Hz, 11H), 4.16-4.32(m, 2H), 5.21 (bs, 1H), 6.67 (dd, J=8.4, 4.4 Hz, 1H), 6.75 (td, J=8.4,3.6 Hz, 1H), 6.81 (dd, J=8.4, 3.2 Hz, 1H).

106e4-(5-Fluoro-2-trifluoromethanesulfonyloxyphenyl)piperidine-1-carboxylicacid t-butyl ester

To a solution of 4-(5-fluoro-2-hydroxyphenyl)piperidine-1-carboxylicacid t-butyl ester (360 mg, 1.22 mmol) produced in Example (106d) intetrahydrofuran (10 mL) was added sodium hydride (60% in oil, 58.6 mg,1.46 mmol) while cooling in an ice bath, the mixture was stirred for 10minutes. To the mixture was addedN-phenylbis(trifluoromethanesulfonimide) (479 mg, 1.34 mmol), followedby stirring for 18 hours at room temperature. Brine was added to thereaction mixture and extraction was performed with ethyl acetate. Theorganic layer was dried over anhydrous magnesium sulfate and thefiltrate was concentrated under reduced pressure to give a residue,which was purified by silica gel column chromatography (ethylacetate/heptane) to give 523 mg of the title compound as a light yellowoil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.25 (s, 9H), 1.40-1.90 (m, 4H), 2.70-2.92(m, 2H), 3.00 (tt, J=12.8, 2.8 Hz, 1H), 4.16-4.34 (m, 2H), 6.88-6.96 (m,2H), 7.01 (dd, J=8.8, 4.8 Hz, 1H).

106f4-[5-Fluoro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperidine-1-carboxylicacid t-butyl ester

To a mixture of4-(5-fluoro-2-trifluoromethanesulfonyloxyphenyl)piperidine-1-carboxylicacid t-butyl ester (523 mg, 1.22 mmol) produced in Example (106e),4,4,5,5-tetramethyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)[1,3,2]dioxaborolane(387 mg, 1.46 mmol) produced in Example (4b) and 1,2-dimethoxyethane (10mL) were added tetrakis(triphenylphosphine)palladium(0) (71 mg, 0.06mmol) and 2N aqueous solution of sodium carbonate (1.83 ml, 3.66 mmol),followed by stirring for 1 hour and 30 minutes at an externaltemperature of 90° C. under a nitrogen atmosphere. Brine was added tothe reaction mixture and extraction was performed with ethyl acetate.The organic layer was dried over anhydrous magnesium sulfate and thefiltrate was concentrated under reduced pressure to give a residue,which was purified by silica gel column chromatography (ethylacetate/heptane) to give 245 mg of the title compound as a light yellowoil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.92 (s, 6H), 1.01 (s, 6H), 1.24 (s, 9H),1.42 (s, 2H), 1.50-1.72 (m, 4H), 1.85 (s, 2H), 2.58-2.98 (m, 3H),4.10-4.32 (m, 2H), 5.25 (s, 1H), 6.76-6.88 (m, 2H), 6.97 (dd, J=8.4, 2.4Hz, 1H).

106g 4-[5-Fluoro-2-(3.3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperidine

To a solution of4-[5-fluoro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperidine-1-carboxylicacid t-butyl ester (245 mg, 0.59 mmol) produced in Example (106f) indichloromethane (3 mL) was added trifluoroacetic acid (3 mL), followedby stirring for 30 minutes at room temperature. The reaction mixture wasconcentrated under reduced pressure, and then saturated aqueous solutionof sodium hydrogencarbonate was added to the obtained residue andextraction was performed with ethyl acetate. The organic layer was driedover anhydrous magnesium sulfate, and the filtrate was concentratedunder reduced pressure to give 220 mg of a crude product of the titlecompound as a light yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 0.92 (s, 6H), 1.01 (s, 6H), 1.42 (s, 2H),1.74-2.40 (m, 6H), 2.76-3.04 (m, 3H), 3.44-3.52 (m, 2H), 5.22 (s, 1H),6.71 (dd, J=10.4, 2.4 Hz, 1H), 6.84 (td, J=8.4, 2.8 Hz, 1H), 6.97 (dd,J=8.4, 2.0 Hz, 1H).

The 1H of NH could not be identified.

MS m/e (ESI) 316 (MH⁺).

106h1-Butyl-4-[5-fluoro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperidinehydrochloride

To a solution of4-[5-fluoro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperidine (70mg, 0.22 mmol) produced in Example (106g) in tetrahydrofuran (2 mL) wereadded butyraldehyde (19.2 mg, 0.27 mmol), sodium triacetoxyborohydride(71 mg, 0.33 mmol) and acetic acid (27 mg, 0.44 mmol), followed bystirring for 15 hours at room temperature. Saturated aqueous solution ofsodium hydrogencarbonate was added to the reaction mixture andextraction was performed with ethyl acetate. The organic layer was driedover anhydrous magnesium sulfate and the filtrate was concentrated underreduced pressure to give a residue, which was purified by NH silica gelcolumn chromatography (ethyl acetate/heptane) to give 55 mg of1-butyl-4-[5-fluoro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperidineas a light yellow oil.

MS m/e (ESI) 372 (MH⁺).

The obtained compound was dissolved in ethyl acetate, and then a 4Nsolution of hydrogen chloride in ethyl acetate was added and the mixturewas stirred for 30 minutes at room temperature. The mixed solution wasconcentrated under reduced pressure, and then hexane was added to theresidue to produce a solid which was then triturated by sonication. Thesolid was filtered and dried under reduced pressure to give 47 mg of thetitle compound as a light yellow solid.

¹H-NMR (400 MHz, CD₃OD) δ: 1.02 (t, J=7.2 Hz, 3H), 1.10 (s, 6H), 1.12(s, 6H), 1.40-1.52 (m, 4H), 1.68-1.80 (m, 2H), 1.92-2.06 (m, 6H),2.82-3.22 (m, 5H), 3.60-3.72 (m, 2H), 5.30 (t, J=1.6 Hz, 1H), 6.93 (td,J=8.4, 2.8 Hz, 1H), 6.99 (dd, J=8.0, 2.4 Hz, 1H), 7.05 (dd, J=8.4, 6.0Hz, 1H). MS m/e (ESI) 372 (MH⁺).

Example 1071-Butyl-4-[5-fluoro-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperidinehydrochloride

To a solution of1-butyl-4-[5-fluoro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperidinehydrochloride (47 mg, 0.12 mmol) produced in Example (106h) in methanol(3 mL) was added 10% palladium on carbon (100 mg, wet), followed bystirring for 4 hours at atmospheric pressure and room temperature undera hydrogen atmosphere. The reaction mixture was filtered through Celite,and the filtrate was concentrated under reduced pressure. Hexane wasadded to the residue to produce a solid, which was then triturated bysonication. The solid was filtered and dried under reduced pressure togive 19 mg of the title compound as a light yellow solid.

¹H-NMR (400 MHz, CD₃OD) δ: 0.97 (s, 6H), 1.03 (t, J=7.2 Hz, 3H),1.08-1.16 (m, 2H), 1.19 (s, 6H), 1.18-1.52 (m, 6H), 1.72-1.84 (m, 2H),1.94-2.10 (m, 4H), 3.06-3.26 (m, 6H), 3.68-3.80 (m, 2H), 6.88-7.02 (m,2H), 7.30 (dd, J=8.8, 6.0 Hz, 1H). MS m/e (ESI) 374 (MH⁺).

Example 1081-[2-(4-Cyclopropylmethylpiperazin-1-yl)phenyl]-3,3,5,5-tetramethylcyclohexanol

108a 1-(2-Bromophenyl)-4-cyclopropylmethylpiperazine

To a solution of 1-(2-bromophenyl)piperazine (3.0 g, 12.4 mmol) intetrahydrofuran (30 mL) were added acetic acid (0.71 mL, 12.4 mmol),cyclopropanecarbaldehyde (1.39 mL, 18.66 mmol) and sodiumtriacetoxyborohydride (4.22 g, 19.9 mmol), followed by stirring for 88hours at room temperature. Aqueous solution of potassium carbonate wasadded to the reaction mixture, extraction was performed with ethylacetate, and the organic layer was concentrated. The resultant residuewas purified by NH silica gel column chromatography (ethylacetate/heptane) to give 3.773 g of the title compound as a colorlessoil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.13-0.16 (m, 2H), 0.52-0.57 (m, 2H),0.87-0.95 (m, 1H), 2.34 (d, J=6.4 Hz, 2H), 2.60-2.85 (br, 4H), 3.03-3.17(br, 4H), 6.88-7.55 (m, 4H).

108b1-[2-(4-Cyclopropylmethylpiperazin-1-yl)phenyl]-3,3,5,5-tetramethylcyclohexanol

To a solution of 1-(2-bromophenyl)-4-cyclopropylmethylpiperazine (700mg, 2.37 mmol) produced in Example (108a) in anhydrous tetrahydrofuran(7 mL) was added dropwise n-butyllithium (1.60 M solution in hexane,1.63 mL, 2.61 mmol) over a period of 3 minutes at an externaltemperature of −70° C. After stirring for 45 minutes under the sameconditions, 3,3,5,5-tetramethylcyclohexanone (0.49 mL, 2.85 mmol) wasadded dropwise to the reaction mixture over a period of 4 minutes at anexternal temperature of −70° C. Stirring was continued for 15 minutesunder the same conditions, and then for 18 hours and 30 minutes whilewarming until the external temperature reached room temperature. Waterwas added to the reaction mixture and extraction was performed withethyl acetate. The separated organic layer was washed with brine andthen dried over anhydrous sodium sulfate. The desiccant was filtered offand the filtrate was concentrated under reduced pressure. The resultantresidue was purified by silica gel column chromatography (ethylacetate/heptane) to give 765 mg of the title compound as a light yellowoil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.12-0.17 (m, 2H), 0.53-0.57 (m, 2H),0.85-0.95 (m, 1H), 0.93 (s, 6H), 1.13-1.79 (m, 6H), 1.38 (s, 6H),2.26-2.33 (m, 2H), 2.34 (d, J=6.4 Hz, 2H), 3.00-3.04 (m, 2H), 3.09-3.14(m, 4H), 7.15 (ddd, J=7.8, 7.8, 1.4 Hz, 1H), 7.22 (ddd, J=7.8, 7.8, 1.4Hz, 1H), 7.31 (dd, J=7.8, 1.4 Hz, 1H), 7.36 (dd, J=7.8, 1.4 Hz, 1H),8.11 (brs, 1H). MS m/e (ESI) 371 (MH⁺).

Example 1091-Cyclopropylmethyl-4-[2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazine

A mixture of1-[2-(4-cyclopropylmethylpiperazin-1-yl)phenyl]-3,3,5,5-tetramethylcyclohexanol(250 mg, 0.675 mmol) produced in Example (108b), water (0.12 mL) andtrifluoroacetic acid (1.04 mL, 13.5 mmol) was stirred for 21 hours at anexternal temperature of room temperature. Aqueous solution of potassiumcarbonate was added to the reaction mixture and then extraction wasperformed with ethyl acetate. Organic layer was concentrated underreduced pressure to give a residue, which was purified by NH silica gelcolumn chromatography (ethyl acetate/heptane) to give 218 mg of thetitle compound as a colorless solid.

¹H-NMR (400 MHz, CDCl₃) δ: 0.11-0.15 (m, 2H), 0.51-0.56 (m, 2H),0.85-0.95 (m, 1H), 1.02 (s, 6H), 1.07 (s, 6H), 1.39 (s, 2H), 2.17 (d,J=1.4 Hz, 2H), 2.29 (d, J=6.4 Hz, 2H), 2.50-2.75 (br, 4H), 2.95-3.10(br, 4H), 5.50 (t, J=1.4 Hz, 1H), 6.95-7.08 (m, 3H), 7.16-7.20 (m, 1H).

Example 1104-{4-[2-(3,3,5,5-Tetramethylcyclohexyl)phenyl]piperazin-1-yl}butan-2-one

A mixture of 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (160mg, 0.532 mmol) produced in Example (8b), methyl vinyl ketone (0.058 mL,0.692 mmol) and chloroform (0.7 mL) was stirred for 21 hours and 30minutes at an external temperature of room temperature. The reactionmixture was diluted with ethyl acetate and then washed with aqueoussolution of sodium hydrogencarbonate. The separated organic layer wasconcentrated under reduced pressure, and the obtained residue waspurified by silica gel column chromatography (ethyl acetate/heptane) togive 155 mg of the title compound as a light brown oil.

MS m/e (ESI) 371 (MH⁺).

Example 1114-[4-[2-(3,3,5,5-Tetramethylcyclohexyl)phenyl]piperazin-1-yl]butan-2-olhydrochloride

To a mixture of4-[4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazin-1-yl]butan-2-one(138 mg, 0.372 mmol) produced in (Example 110) and methanol (1.5 mL) wasgradually added sodium borohydride (14.1 mg, 0.372 mmol) at an externaltemperature of room temperature, followed by stirring for 2 hours underthe same conditions. Aqueous solution of ammonium chloride was added tothe reaction mixture, and stirring was continued for 20 minutes. Aftermaking the mixture basic with aqueous solution of potassium carbonate,extraction was performed with ethyl acetate. The separated organic layerwas concentrated under reduced pressure to give a residue, which waspurified by NH silica gel column chromatography (ethyl acetate/heptane)to give 136 mg of the free form of the title compound as a colorlessoil. The free from of the title compound (19 mg, 0.051 mmol) wasdissolved in a mixed solvent of ethyl alcohol and ethyl acetate, andthen a 4N solution of hydrogen chloride in ethyl acetate (0.014 mL,0.056 mmol) was added. The mixed solution was concentrated under reducedpressure and the resulting solid residue was washed with a diethylether-heptane mixed solvent and then dried under reduced pressure togive 21 mg of the title compound as a colorless solid.

MS m/e (ESI) 373 (MH⁺).

Example 1121-(3-Fluorobutyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

To a solution of4-[4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazin-1-yl]butan-2-ol(40 mg, 0.107 mmol) produced as an intermediate in Example 111 indichloromethane (1 mL) was added diethylaminosulfur trifluoride (DAST)(0.017 mL, 0.128 mmol) at an external temperature of −70° C. The mixturewas then stirred for 15 hours while heating until the externaltemperature reached room temperature. The reaction mixture was thencooled to an external temperature of 0° C., aqueous solution ofpotassium carbonate was added and the mixture was stirred. The mixturewas extracted with ethyl acetate to give an organic layer which wasdried over anhydrous sodium sulfate. The desiccant was filtered off andthe filtrate was concentrated under reduced pressure. The resultantresidue was purified by NH silica gel column chromatography (ethylacetate/heptane) to give 2.8 mg of1-(3-fluorobutyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazineas a colorless oil. This compound was dissolved in ethyl acetate-ethanoland a 4N solution of hydrogen chloride in ethyl acetate (0.002 mL) wasadded. The reaction mixture was concentrated under reduced pressure, andthe obtained solid residue was washed with a diethyl ether-heptane mixedsolvent and then dried under reduced pressure to give 2.7 mg of thetitle compound as a colorless solid.

MS m/e (ESI) 375 (MH⁺).

Example 1131-{4-[2-(3,3,5,5-Tetramethylcyclohexyl)phenyl]piperazin-1-yl}hexan-2-olhydrochloride

A mixture of 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (120mg, 0.399 mmol) produced in Example (8b), 1,2-epoxyhexane (240 mg, 2.39mmol) and 2-propanol (0.8 mL) was stirred for 18 hours at an externaltemperature of 80° C. The reaction mixture was concentrated underreduced pressure to give a residue, which was purified by NH silica gelcolumn chromatography (ethyl acetate/heptane) to give 116 mg of1-{4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazin-1-yl}hexan-2-olas a light yellow solid. This compound (12 mg, 0.030 mmol) was dissolvedin diethyl ether and a 4N solution of hydrogen chloride in ethyl acetate(0.0083 mL, 0.033 mmol) was added. The mixed solution was concentratedunder reduced pressure and the obtained solid residue was washed with adiethyl ether-heptane mixed solvent and then dried under reducedpressure to give 10 mg of the title compound as a colorless solid.

MS m/e (ESI) 401 (MH⁺).

Example 1141-{4-[2-(3,3,5,5-Tetramethylcyclohexyl)phenyl]piperazin-1-yl}butan-2-olhydrochloride

To a mixture of1-{4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazin-1-yl}butan-2-one(298 mg, 0.802 mmol) produced as an intermediate in Example 25 andmethanol (3 mL) was gradually added sodium borohydride (36.4 mg, 0.962mmol) at an external temperature of room temperature, followed bystirring for 1 hour under the same conditions. Aqueous solution ofammonium chloride was added to the reaction mixture and the mixture wasstirred overnight and the mixture was made basic with aqueous solutionof potassium carbonate, and extraction was performed with ethyl acetate.The separated organic layer was concentrated under reduced pressure togive a residue, which was purified by NH silica gel columnchromatography (ethyl acetate/heptane) to give 269 mg of the free formof the title compound as a colorless solid. The free form of the titlecompound (20 mg, 0.054 mmol) was dissolved in a mixed solvent of ethanoland ethyl acetate, and then a 4N solution of hydrogen chloride in ethylacetate (0.015 mL, 0.059 mmol) was added. The mixed solution wasconcentrated under reduced pressure and the resulting solid residue waswashed with a mixed solvent of diethyl ether and heptane and then driedunder reduced pressure to give 20 mg of the title compound as acolorless solid.

MS m/e (ESI) 373 (MH⁺).

Example 1152-{4-[2-(3,3,5,5-Tetramethylcyclohexyl)phenyl]piperazin-1-ylmethyl}butyronitrilehydrochloride

To a mixture of1-{4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazin-1-yl}butan-2-one(80 mg, 0.216 mmol) produced as an intermediate in Example 25,1,2-dimethoxyethane (2.5 mL) and t-butanol (0.1 mL) were addedp-toluenesulfonylmethyl isocyanide (TosMIC) (46.4 mg, 0.238 mmol) andpotassium t-butoxide (34 mg, 0.302 mmol) at an external temperature of0° C., followed by stirring for 90 minutes under the same conditions.The external temperature was then raised to room temperature andstirring was continued for 30 minutes. Brine was added to the reactionmixture, extraction was performed with ethyl acetate, and the obtainedorganic layer was dried over anhydrous sodium sulfate. After removingthe desiccant by filtration, the filtrate was concentrated under reducedpressure to give a residue, which was then purified by NH silica gelcolumn chromatography (ethyl acetate/heptane) to give 66 mg of the freeform of the title compound as a colorless oil. This compound (66 mg,0.173 mmol) was dissolved in dichloromethane-ethyl acetate, and then a4N solution of hydrogen chloride in ethyl acetate (0.046 mL, 0.18 mmol)was added. The mixed solution was concentrated under reduced pressure,and the resulting solid residue was washed with a diethyl ether-heptanemixed solvent and then dried under reduced pressure to give 65 mg of thetitle compound as a colorless solid.

MS m/e (ESI) 382 (MH⁺).

Example 1161-Furan-3-ylmethyl-4-[2-(3,3,5,5-tetramethlcyclohexyl)phenyl]piperazinehydrochloride

To a mixture of 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine(50 mg, 0.166 mmol) produced in Example (8b), furan-3-carbaldehyde (0.02mL, 0.231 mmol) and tetrahydrofuran (3 mL) was added sodiumtriacetoxyborohydride (43 mg, 0.203 mmol), followed by stirring for 20minutes at room temperature. Saturated aqueous solution of sodiumhydrogencarbonate was added to the reaction mixture and extraction wasperformed with ethyl acetate. The solvent was distilled off by nitrogenstream. The resultant residue was purified by NH silica gel columnchromatography (ethyl acetate/hexane) to give1-furan-3-ylmethyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine.This compound was dissolved in dichloromethane, and a 4N solution ofhydrogen chloride in ethyl acetate was added. The solvent was distilledoff by nitrogen stream. Diethyl ether was added to the obtained residueto produce a solid, and after further adding hexane, the solid wastriturated by sonication. The supernatant solution was removed and theobtained solid was dried to give 33 mg of the title compound ascolorless crystals.

MS m/e (ESI) 381 (MH⁺).

Example 1171-Cyclopropylmethyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinemethanesulfonate

117a Trifluoromethanesulfonic acid 3,3,5,5-tetramethylcyclohex-1-enylester

3,3,5,5-Tetramethylcyclohexanone (100.0 g, 648.3 mmol) was dissolved inanhydrous tetrahydrofuran (750 mL) under a nitrogen atmosphere, and themixture was cooled and stirred at an external temperature of below −70°C. To the mixture was added dropwise bis(trimethylsilyl)amide lithium(1M solution in tetrahydrofuran, 778 mL, 778 mmol) over a period of 30minutes under the same conditions, followed by stirring for 70 minutesunder the same conditions. Then, a solution ofN-phenylbis(trifluoromethanesulfonimide) (254.8 g, 713 mmol) inanhydrous tetrahydrofuran (1 L) was added dropwise to the reactionmixture over a period of 35 minutes. After stirring the mixture for 20minutes under the same conditions, the mixture was stirred for 15 hourswhile gradually warmed to an external temperature of room temperature.Reaction was repeated twice more on the same scale as above, by the sameprocedure under the same reaction conditions. The three reactionmixtures were combined and subjected to the following treatment.

Ethyl acetate (1.5 L) was added to the combined reaction mixture, andthen a solution of concentrated hydrochloric acid (450 mL) in ice water(5 L) was added while stirring. After stirring for a while, theseparated organic layer was washed with brine (1.5 L), saturated aqueoussolution of sodium hydrogencarbonate (1.5 L) and brine (1.5 L). Theobtained organic layer was dried over anhydrous magnesium sulfate (1.5kg) for 30 minutes while stirring. The desiccant was filtered off andthe filtrate was concentrated under reduced pressure. The resultantresidue was purified by silica gel column chromatography (hexane) andthen dried under reduced pressure to give 520.94 g of the title compoundas a light yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.05 (s, 6H), 1.10 (s, 6H), 1.35 (s, 2H),2.09 (d, J=1.2 Hz, 2H), 5.51 (t, J=1.2 Hz, 1H).

117b 1-Nitro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)benzene

To a mixture of trifluoromethanesulfonic acid3,3,5,5-tetramethylcyclohex-1-enyl ester (160.0 g, 558.8 mmol),2-nitrophenylboronic acid

(97.9 g, 586.8 mmol) and 1,2-dimethoxyethane (920 mL) were added sodiumcarbonate (118.5 g, 1.12 mol) and purified water (230 mL) while stirringat room temperature. Then, tetrakis(triphenylphosphine)palladium(0)(29.1 g, 25.1 mmol) was added to the mixture at room temperature (in anoil bath at room temperature), and the inside of the flask was replacedwith nitrogen gas. The mixture was then stirred for 4 hours and 30minutes at an external temperature of room temperature (in an oil bathat room temperature).

The same reaction was then repeated twice more by the same procedureunder the same reaction conditions as above, but with an amount of 170.0g (593.7 mmol) of trifluoromethanesulfonic acid3,3,5,5-tetramethylcyclohex-1-enyl ester, a starting material, and theamounts of the other reagents changed to corresponding equivalents. Thethree reaction mixtures were combined and subjected to the followingtreatment.

Ethyl acetate (1.5 L) and water (4 L) were added to the combinedreaction mixture, which was then stirred for 5 minutes. The mixture wasfiltered through Celite to remove insoluble materials. After stirringthe obtained filtrate for a while, the organic layer was separated andthe aqueous layer was extracted with ethyl acetate (1 L). The organiclayers were combined and then dried over anhydrous magnesium sulfate (1kg) for 20 minutes while stirring. The desiccant was filtered off andthe filtrate was concentrated under reduced pressure. The resultantresidue was purified by silica gel column chromatography (ethylacetate/hexane) and then dried under reduced pressure to give 407.30 gof the title compound as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 1.046 (s, 6H), 1.053 (s, 6H), 1.41 (s, 2H),2.02 (d, J=1.6 Hz, 2H), 5.37 (t, J=1.6 Hz, 1H), 7.26 (dd, J=7.6, 1.6 Hz,1H), 7.33 (ddd, J=8.0, 7.6, 1.6 Hz, 1H), 7.49 (ddd, J=7.6, 7.6, 1.2 Hz,1H), 7.74 (dd, J=8.0, 1.2 Hz, 1H).

117c 2-(3,3,5,5-Tetramethylcyclohexyl)phenylamine

A mixture of 1-nitro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)benzene(130.0 g, 501.3 mmol), 10% palladium on carbon (13.0 g, wet) and ethylalcohol (1820 mL) was placed in a flask, then the inside of the flaskwas replaced with hydrogen, and the mixture was stirred for 78 hours atroom temperature under a hydrogen atmosphere at atmospheric pressure.Reaction was repeated two more times on the same scale as above, by thesame procedure under the same reaction conditions. The three reactionmixtures were combined and subjected to the following treatment.

The combined reaction mixture was filtered, and the filtrate wasconcentrated under reduced pressure. The obtained residue was dilutedwith ethyl acetate (700 mL) and hexane (200 mL), and then dried overanhydrous sodium sulfate (200 g) for 20 minutes while stirring. Thedesiccant was filtered off using a glass microfiber filter, and then thefiltrate was concentrated and dried under reduced pressure to give345.76 g of the title compound as a light brown oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.95 (s, 6H), 1.13 (s, 6H), 1.08-1.36 (m,4H), 1.59-1.62 (m, 2H), 2.86 (tt, J=12.4, 2.8 Hz, 1H), 3.63 (brs, 2H),6.70 (dd, J=7.6, 1.2 Hz, 1H), 6.78 (ddd, J=7.6, 7.6, 1.2 Hz, 1H), 7.02(ddd, J=7.6, 7.6, 1.2 Hz, 1H), 7.12 (dd, J=7.6, 1.2 Hz, 1H).

117d 1-[2-(3,3,5,5-Tetramethylcyclohexyl)phenyl]piperazine

To a mixture of 2-(3,3,5,5-tetramethylcyclohexyl)phenylamine (168.0 g,726.1 mmol) and 1,2-dichlorobenzene (1200 mL) was addedbis(2-chloroethyl)amine hydrochloride (155.5 g, 871.3 mmol). The mixturewas stirred for 7 hours at an external temperature of 190° C. under anitrogen atmosphere. During the reaction, a nitrogen stream was passedthrough the reactor several times to remove the generated hydrogenchloride gas. Reaction was repeated once more on the same scale asabove, by the same procedure under the same reaction conditions. The tworeaction mixtures were combined and subjected to the followingtreatment.

After cooling to room temperature, the combined reaction mixture wasdiluted with ethyl acetate (6 L) and water (1 L). The mixture was thenadded to a mixture of potassium carbonate (1.3 kg) and water (5 L) whilestirring. The mixture was stirred and allowed to stand, and the organiclayer was separated. The aqueous layer was again extracted with ethylacetate (2 L). The combined organic layers were washed with brine (3 L)and then dried over anhydrous sodium sulfate (3.5 kg). The desiccant wasfiltered off and the filtrate was concentrated under reduced pressure.The resultant residue was purified by NH silica gel columnchromatography (ethyl acetate/hexane) and then dried under reducedpressure to give 241.67 g of the title compound as a light pink solid.

In addition to this, the above NH silica gel column chromatographypurification also yielded 126.2 g of an oil as a mixture of the targetcompound and impurities. Hexane (150 mL) was added to the oil, and themixture was stirred for 2 hours at 0° C. The produced precipitate wascollected by suction filtration and then dried under reduced pressure togive 42.74 g of the title compound as a light pink solid. A total of284.41 g of the title compound was obtained as a light pink solid.

¹H-NMR (400 MHz, CDCl₃) δ: 0.93 (s, 6H), 1.13 (s, 6H), 1.17-1.35 (m,4H), 1.42-1.46 (m, 2H), 2.84-2.87 (m, 4H), 3.02-3.04 (m, 4H), 3.60 (tt,J=12.8, 2.8 Hz, 1H), 7.06-7.18 (m, 3H), 7.23 (dd, J=7.6, 1.6 Hz, 1H).

The 1H of NH could not be identified.

117f1-Cyclopropylmethyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine

To a mixture of 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine(241.67 g, 804.3 mmol), acetic acid (46.0 mL, 804.3 mmol) andtetrahydrofuran (3300 mL) was added a mixed solution ofcyclopropanecarbaldehyde (64.8 g, 924.9 mmol) and tetrahydrofuran (200mL) while stirring at an external temperature of room temperature. Afterstirring for 10 minutes, sodium triacetoxyborohydride (238.6 g, 1126mmol) was added portionwise to the reaction mixture over a period of 8minutes. The mixture was then stirred for 3 hours at an externaltemperature of room temperature.

The reaction mixture was diluted with hexane (2 L) and water (1 L). Thismixture was then added to a mixture of potassium carbonate (667 g) andwater (3.5 L) while stirring. After stirring for a while and allowingthe mixture to stand, the separated organic layer was washedsequentially with water (2 L) and brine (1.5 L). The organic layer wasthen dried over anhydrous sodium sulfate (1.5 kg), the desiccant wasfiltered off, and the obtained filtrate was concentrated under reducedpressure. The obtained residue was purified by NH silica gel columnchromatography (ethyl acetate/hexane) and then concentrated underreduced pressure to give an oil. The oil was dissolved again in ethylacetate (1 L), and the mixture was filtered through a glass microfibrefilter to remove insoluble materials. The obtained filtrate wasconcentrated under reduced pressure, and then a vacuum pump was used fordrying under reduced pressure for 2 hours at an external temperature of50° C., to give 280.7 g of the title compound as crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 0.12-0.16 (m, 2H), 0.52-0.56 (m, 2H),0.88-0.96 (m, 1H), 0.92 (s, 6H), 1.12 (s, 6H), 1.13-1.34 (m, 4H),1.41-1.47 (m, 2H), 2.32 (d, J=6.4 Hz, 2H), 2.40-2.98 (br, 4H), 2.94-2.96(m, 4H), 3.58 (tt, J=12.6, 2.8 Hz, 1H), 7.05-7.18 (m, 3H), 7.22-7.24 (m,1H).

117g1-Cyclopropylmethyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinemethanesulfonate

A mixture of1-cyclopropylmethyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine(277.0 g, 781.2 mmol) and methyl ethyl ketone (2493 mL) was stirredwhile heating at an external temperature of 81° C. Methanesulfonic acid(76.58 g, 796.8 mmol) was then added dropwise thereto over a period of 3minutes, to form a thoroughly dissolved state. After heating andstirring for 7 minutes at an external temperature of 81° C., theexternal temperature was gradually lowered and stirring was continueduntil the internal temperature reached 37° C. The reaction suspensioncontaining the produced precipitate was transferred to another flaskusing methyl ethyl ketone (100 mL). The suspension was then concentratedunder reduced pressure over a period of 1 hour and 20 minutes at anexternal temperature of 21° C. It was then dried under reduced pressurefor 30 minutes at an external temperature of 40° C. for solidificationof the flask contents, to give a crude solid product of the titlecompound. After adding a mixed solvent of ethyl acetate (1662 mL) andheptane (1108 mL) to this crude solid product, the resulting suspensionwas stirred for 1 hour at an external temperature of 65° C. Thesuspension was then further stirred while gradually lowering theexternal temperature, and after the external temperature reached 45° C.,stirring was continued for 14 hours at an external temperature of roomtemperature. The obtained suspension was filtered and the precipitatedsolid was collected. The solid was washed with a mixed solvent of ethylacetate (330 mL) and heptane (220 mL) and aircured by aspiration for 4hours at room temperature. The obtained crystals were dried for 6 hoursat 70° C. in a warm-air drier to give 335.9 g of the title compound ascolorless (white) powdery crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 0.47-0.51 (m, 2H), 0.81-0.85 (m, 2H), 0.94(s, 6H), 1.10 (s, 6H), 1.15-1.43 (m, 7H), 2.85 (s, 3H), 2.95-3.11 (m,6H), 3.43 (tt, J=12.6, 3.0 Hz, 1H), 3.52-3.61 (m, 2H), 3.80 (br d,J=11.2 Hz, 2H), 7.13-7.26 (m, 4H), 11.11 (br s, 1H).

Example 118

The following compounds were produced according to the common productionmethods described above, the methods described in the examples, orcombinations thereof with well-known methods.

2-{4-[2-(4-t-Butylcyclohexyl)phenyl]piperazin-1-yl}-N-propylacetamidehydrochloride

MS m/e (ESI) 400 (MH⁺).

2-{4-[2-(4-t-Butylcyclohexyl)phenyl]piperazin-1-yl}-N,N-dimethylacetamidehydrochloride

MS m/e (ESI) 386 (MH⁺).

4-Benzyl-1-[2-(4-t-butylcyclohexyl)phenyl]piperazin-2-one hydrochloride

MS m/e (ESI) 405 (MH⁺).

2-{4-[2-(4-t-Butylcyclohex-1-enyl)phenyl]piperazin-1-yl}-N-ethylacetamidehydrochloride

MS m/e (ESI) 384 (MH⁺).

1-[2-(4-t-Butylcyclohexyl)phenyl]-4-cyclopropylmethylpiperazinehydrochloride

MS m/e (ESI) 355 (MH⁺).

1-[2-(4-t-Butylcyclohex-1-enyl)phenyl]-4-methylpiperazine hydrochloride

MS m/e (ESI) 313 (MH⁺).

1-Furan-3-ylmethyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 381 (MH⁺).

1-[4-(4-Methoxypiperidin-1-yl)-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]-4-propylpiperazinehydrochloride

MS m/e (ESI) 454 (MH⁺).

2-{4-[2-(4-t-Butylcyclohexyl)phenyl]piperazin-1-yl}-1-morpholin-4-ylethanonehydrochloride

MS m/e (ESI) 428 (MH⁺).

2-{4-[2-(4-t-Butylcyclohexyl)phenyl]piperazin-1-yl}-1-pyrrolidin-1-ylethanonehydrochloride

MS m/e (ESI) 412 (MH⁺).

1-Azepan-1-yl-2-{4-[2-(4-t-butylcyclohexyl)phenyl]piperazin-1-yl}ethanonehydrochloride

MS m/e (ESI) 440 (MH⁺).

3-(4-t-Butylcyclohexyl)-4-(4-butylpiperazine-1-yl)benzonitrilehydrochloride

MS m/e (ESI) 382 (MH⁺).

1-Butyl-4-[2-(4-t-butylcyclohexyl)-4-pyridin-2-ylphenyl]piperazinehydrochloride

MS m/e (ESI) 434 (MH⁺).

4-(4-t-Butylcyclohex-1-enyl)-3-(4-butylpiperazine-1-yl)phenylaminehydrochloride

MS m/e (ESI) 370 (MH⁺).

[4-(4-t-Butylcyclohex-1-enyl)-3-(4-butylpiperazine-1-yl)phenyl]dimethylaminehydrochloride

MS m/e (ESI) 398 (MH⁺).

[4-(4-t-Butylcyclohexyl)-3-(4-butylpiperazine-1-yl)phenyl]dimethylaminehydrochloride

MS m/e (ESI) 400 (MH⁺).

1-[4-(4-Methoxypiperidin-1-yl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]-4-pentylpiperazinehydrochloride

MS m/e (ESI) 482 (MH⁺).

1-[2-(4-t-Butylcyclohex-1-enyl)-4-(4-methoxypiperidin-1-yl)phenyl]-4-propylpiperazinehydrochloride

MS m/e (ESI) 454 (MH⁺).

1-Butyl-4-[2-(4-t-butylcyclohexyl)-4-(4-methoxypiperidin-1-yl)phenyl]piperazinehydrochloride

MS m/e (ESI) 470 (MH⁺).

1-[4-(4-Methoxypiperidin-1-yl)-2-spiro[5.5]undec-2-en-3-ylphenyl]-4-pentylpiperazinehydrochloride

MS m/e (ESI) 494 (MH⁺).

1-[4-(2-Spiro[5.5]undec-3-ylphenyl)piperazin-1-yl]butan-2-onehydrochloride

MS m/e (ESI) 383 (MH⁺).

1-Butyl-4-[2-(4-butylcyclohexyl)phenyl]piperazine hydrochloride

MS m/e (ESI) 357 (MH⁺).

[4-(4-t-Butylcyclohexyl)-3-(4-butylpiperazine-1-yl)phenyl]acetic acidmethyl ester hydrochloride

MS m/e (ESI) 429 (MH⁺).

[5-(4-t-Butylcyclohexyl)-4-(4-butylpiperazine-1-yl)-2-methoxyphenyl]dimethylaminehydrochloride

MS m/e (ESI) 430 (MH⁺).

1-Cyclopropylmethyl-4-[2-(4,4-diethylcyclohex-1-enyl)-5-methoxyphenyl]piperazinehydrochloride

MS m/e (ESI) 383 (MH⁺).

1-Cyclopropylmethyl-4-[2-(4,4-diethylcyclohexyl)-5-methoxy]phenyl]piperazinehydrochloride

MS m/e (ESI) 385 (MH⁺).

1-[2-(4,4-Diethylcyclohex-1-enyl)-5-methoxyphenyl]-4-propylpiperazinehydrochloride

MS m/e (ESI) 371 (MH⁺).

[4-(4-Butylpiperazin-1-yl)-5-(4,4-dimethylcyclohexyl)-2-methoxyphenyl]dimethylaminehydrochloride

MS m/e (ESI) 430 (MH⁺).

1-Propyl-4-(2-spiro[4.5]dec-7-en-8-ylphenyl)piperazine hydrochloride

MS m/e (ESI) 339 (MH⁺).

1-Propyl-4-(2-spiro[4.5]dec-8-ylphenyl)piperazine hydrochloride

MS m/e (ESI) 341 (MH⁺).

1-(2-Spiro[4.5]dec-8-ylphenyl)-4-(tetrahydropyran-4-ylmethyl)piperazinehydrochloride

MS m/e (ESI) 397 (MH⁺).

[4-(4-Butylpiperazin-1-yl)-2-methoxy-5-(3,3,5,5-tetramethylcyclohexyl)phenyl]dimethylaminehydrochloride

MS m/e (ESI) 430 (MH⁺).

4-[4-(4-Pentylpiperazin-1-yl)-3-spiro[4.5]dec-7-en-8-ylphenyl]morpholinehydrochloride

MS m/e (ESI) 452 (MH⁺).

1-Butyl-4-[2-(4-t-butylcyclohexyl)-5-methoxyphenyl]piperazinehydrochloride

MS m/e (ESI) 387 (MH⁺).

1-Butyl-4-[2-(4-t-butylcyclohexyl)-4-methoxyphenyl]piperazinehydrochloride

MS m/e (ESI) 387 (MH⁺).

2-{4-[2-(4-t-Butylcyclohexyl)-4-methoxyphenyl]piperazin-1-yl}-N,N-dimethylacetamidehydrochloride

MS m/e (ESI) 416 (MH⁺).

3-{4-[2-(4-t-Butylcyclohexyl)phenyl]piperazin-1-yl}propionic acid methylester

MS m/e (ESI) 387 (MH⁺).

4-[4-(4-t-Butylcyclohexyl)-3-(4-butylpiperazin-1-yl)phenyl]morpholinehydrochloride

MS m/e (ESI) 442 (MH⁺).

1-[4-(4-t-Butylcyclohexyl)-3-(4-butylpiperazin-1-yl)phenyl]ethanonehydrochloride

MS m/e (ESI) 399 (MH⁺).

4-[3-(4,4-Dimethylcyclohex-1-enyl)-4-(4-isobutylpiperazine-1-yl)-phenyl]morpholinehydrochloride

MS m/e (ESI) 412 (MH⁺).

cis-4-[4-(4-Butylpiperazin-1-yl)-3-(4,4-dimethylcyclohexyl)phenyl]-2,6-dimethylmorpholinehydrochloride

MS m/e (ESI) 442 (MH⁺).

4-[4-(4-Butylpiperazin-1-yl)-3-(4,4-dimethylcyclohex-1-enyl)phenyl]morpholinehydrochloride

MS m/e (ESI) 412 (MH⁺).

4-[3-(4,4-Dimethylcyclohex-1-enyl)-4-(4-propylpiperazin-1-yl)phenyl]morpholinehydrochloride

MS m/e (ESI) 398 (MH⁺).

1-Butyl-4-[2-(4,4-dimethylcyclohex-1-enyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 327 (MH⁺).

4-[3-(4-t-Butylcyclohexyl)-4-(4-butylpiperazine-1-yl)phenyl]morpholinehydrochloride

MS m/e (ESI) 442 (MH⁺).

4-[2-(4,4-Dimethylcyclohexyl)phenyl]piperazine-1-carboxylic acid ethylester

MS m/e (ESI) 345 (MH⁺).

1-[2-(4-t-Butylcyclohex-1-enyl)phenyl]-4-(2-methoxyethyl)piperazinehydrochloride

MS m/e (ESI) 357 (MH⁺).

4-[4-(4-Butylpiperazin-1-yl)-3-(4,4-dimethylcyclohexyl)phenyl]morpholinehydrochloride

MS m/e (ESI) 414 (MH⁺).

1-[2-(4-t-Butylcyclohexyl)phenyl]-4-(tetrahydropyran-4-ylmethyl)piperazinehydrochloride

MS m/e (ESI) 399 (MH⁺).

1-[2-(4-t-Butylcyclohexyl)phenyl]-4-furan-2-ylmethylpiperazinehydrochloride

MS m/e (ESI) 381 (MH⁺).

1-[2-(4-t-Butylcyclohexyl)phenyl]-4-furan-3-ylmethylpiperazinehydrochloride

MS m/e (ESI) 381 (MH⁺).

1-{4-[2-(4,4-Dimethylcyclohex-1-enyl)phenyl]piperazin-1-yl}butan-2-onehydrochloride

MS m/e (ESI) 341 (MH⁺).

4-[3-(4-t-Butylcyclohex-1-enyl)-4-(4-pentylpiperazin-1-yl)phenyl]morpholinehydrochloride

MS m/e (ESI) 454 (MH⁺).

1-Butyl-4-(2-spiro[2.5]oct-5-en-6-ylphenyl)piperazine hydrochloride

MS m/e (ESI) 325 (MH⁺).

4-[4-(4-Butylpiperazin-1-yl)-3-(4,4-dimethylcyclohexyl)phenyl]morpholinehydrochloride

MS m/e (ESI) 442 (MH⁺).

4-[4-(4-Butylpiperazin-1-yl)-3-spiro[5.5]undec-3-ylphenyl]morpholinehydrochloride

MS m/e (ESI) 454 (MH⁺).

1-[2-(4,4-Diethylcyclohexyl)phenyl]-4-propylpiperazine hydrochloride

MS m/e (ESI) 343 (MH⁺).

1-Cyclopropylmethyl-4-[2-(4,4-dimethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 355 (MH⁺).

1-[2-(4,4-Diethylcyclohex-1-enyl)-4-(4-methoxypiperidin-1-yl)pheny]-4-propylpiperazinehydrochloride

MS m/e (ESI) 454 (MH⁺).

1-[2-(4,4-Diethylcyclohexyl)-4-(4-methoxypiperidin-1-yl)phenyl]-4-pentylpiperazinehydrochloride

MS m/e (ESI) 484 (MH⁺).

1-{4-[2-(4,4-Diethylcyclohexyl)phenyl]piperazin-1-yl}butan-2-onehydrochloride

MS m/e (ESI) 371 (MH⁺).

1-Butyl-4-[2-(4,4-dimethylcyclohexyl)phenyl]piperazine hydrochloride

MS m/e (ESI) 357 (MH⁺).

4-[3-(4,4-Diethylcyclohex-1-enyl)-4-(4-propylpiperazin-1-yl)phenyl]morpholinehydrochloride

MS m/e (ESI) 426 (MH⁺).

4-{3-(4,4-Diethylcyclohex-1-enyl)-4-[4-(tetrahydropyran-4-ylmethyl)piperazin-1-yl]phenyl}morpholinehydrochloride

MS m/e (ESI) 482 (MH⁺).

1-{2-(4-t-Butylcyclohexyl)-4-(4-methoxypiperidin-1-yl)phenyl}-4-propylpiperazinehydrochloride

MS m/e (ESI) 456 (MH⁺).

1-{2-(4-t-Butylcyclohexyl)-4-(4-methoxypiperidin-1-yl)phenyl}-4-cyclopropylmethylpiperazinehydrochloride

MS m/e (ESI) 468 (MH⁺).

1-Propyl-4-(2-spiro[5.5]undec-2-en-3-ylphenyl)piperazine hydrochloride

MS m/e (ESI) 353 (MH⁺).

1-Cyclopropylmethyl-4-(2-spiro[5.5]undec-2-en-3-ylphenyl)piperazinehydrochloride

MS m/e (ESI) 365 (MH⁺).

4-{4-(4-Butylpiperazin-1-yl)-3-spiro[5.5]undec-2-en-3-ylphenyl}morpholinehydrochloride

MS m/e (ESI) 452 (MH⁺).

4-{4-(4-Propylpiperazin-1-yl)-3-spiro[5.5]undec-2-en-3-ylphenyl}morpholinehydrochloride

MS m/e (ESI) 438 (MH⁺).

4-{4-(4-Cyclopropylmethylpiperazin-1-yl)-3-spiro[5.5]undec-2-en-3-ylphenyl}morpholinehydrochloride

MS m/e (ESI) 450 (MH⁺).

4-[4-{4-(3-Methylbutyl)piperazin-1-yl}-3-spiro[5.5]undec-2-en-3-ylphenyl]morpholinehydrochloride

MS m/e (ESI) 466 (MH⁺).

4-[3-Spiro[5.5]undec-2-en-3-yl-4-{4-(tetrahydropyran-4-ylmethyl)piperazin-1-yl}phenyl]morpholinehydrochloride

MS m/e (ESI) 494 (MH⁺).

4-{4-(4-Pentylpiperazin-1-yl)-3-spiro[0.5]undec-2-en-3-ylphenyl}morpholinehydrochloride

MS m/e (ESI) 466 (MH⁺).

1-(2-Methoxyethyl)-4-(2-spiro[0.5]undec-2-en-3-ylphenyl)piperazinehydrochloride

MS m/e (ESI) 369 (MH⁺).

1-{4-(2-Spiro[0.5]undec-2-en-3-ylphenyl)piperazin-1-yl}butan-2-onehydrochloride

MS m/e (ESI) 381 (MH⁺).

1-Propyl-4-(2-spiro[5.5]undec-3-ylphenyl)piperazine hydrochloride

MS m/e (ESI) 355 (MH⁺).

1-Cyclopropylmethyl-4-(2-spiro[5.5]undec-3-ylphenyl)piperazinehydrochloride

MS m/e (ESI) 367 (MH⁺).

1-(3-Methylbutyl)-4-(2-spiro[5.5]undec-3-ylphenyl)piperazinehydrochloride

MS m/e (ESI) 383 (MH⁺).

1-Butyl-4-{4-(4-methoxypiperidin-1-yl)-2-spiro[5.5]undec-2-en-3-ylphenyl}piperazinehydrochloride

MS m/e (ESI) 480 (MH⁺).

4-[4-{4-(3-Methylbutyl)piperazin-1-yl}-3-spiro[5.5]undec-3-ylphenyl]morpholinehydrochloride

MS m/e (ESI) 468 (MH⁺).

4-[3-Spiro[5.5]undec-3-yl-4-{4-(tetrahydropyran-4-ylmethyl)piperazin-1-yl}phenyl]morpholinehydrochloride

MS m/e (ESI) 496 (MH⁺).

1-{4-(4-Morpholin-4-yl-2-spiro[5.5]undec-3-ylphenyl)piperazin-1-yl}butan-2-onehydrochloride

MS m/e (ESI) 468 (MH⁺).

1-(2-Methoxyethyl)-4-{4-(4-methoxypiperidin-1-yl)-2-spiro[5.5]undec-3-ylphenyl}piperazinehydrochloride

MS m/e (ESI) 484 (MH⁺).

1-Butyl-4-{4-(4-methoxypiperidin-1-yl)-2-spiro[2.5]oct-5-en-6-ylphenyl}piperazinehydrochloride

MS m/e (ESI) 438 (MH⁺).

1-{4-(4-Methoxypiperidin-1-yl)-2-spiro[2.5]oct-5-en-6-ylphenyl}-4-pentylpiperazinehydrochloride

MS m/e (ESI) 452 (MH⁺).

4-{4-(4-Isobutylpiperazine-1-yl)-3-spiro[2.5]oct-5-en-6-ylphenyl}morpholinehydrochloride

MS m/e (ESI) 410 (MH⁺).

4-{4-(4-Isobutylpiperazine-1-yl)-3-spiro[2.5]oct-6-ylphenyl}morpholinehydrochloride

MS m/e (ESI) 412 (MH⁺).

4-{4-(4-Pentylpiperazin-1-yl)-3-spiro[2.5]oct-6-ylphenyl}morpholinehydrochloride

MS m/e (ESI) 426 (MH⁺).

(S)-1-Butyl-4-{2-(4,4-dimethylcyclohexyl)-4-(3-methoxypiperidin-1-yl)phenyl}piperazinehydrochloride

MS m/e (ESI) 442 (MH⁺).

(R)-1-Cyclopropylmethyl-4-{2-(4,4-dimethylcyclohexyl)-4-(3-methoxypiperidin-1-yl)phenyl}piperazinehydrochloride

MS m/e (ESI) 468 (MH⁺).

1-Isopropyl-4-{2-(3,3,5,5-tetramethylcyclohexyl)phenyl}piperazinehydrochloride

MS m/e (ESI) 343 (MH⁺).

1-Cyclopentyl-4-{2-(3,3,5,5-tetramethylcyclohexyl)phenyl}piperazinehydrochloride

MS m/e (ESI) 369 (MH⁺).

1-(2-Cycloheptylphenyl)-4-propylpiperazine hydrochloride

MS m/e (ESI) 301 (MH⁺).

1-(2-Cycloheptylphenyl)-4-cyclopropylmethylpiperazine hydrochloride

MS m/e (ESI) 313 (MH⁺).

1-(2-Cycloheptylphenyl)-4-isobutylpiperazine hydrochloride

MS m/e (ESI) 315 (MH⁺).

1-(2-Cycloheptylphenyl)-4-(tetrahydropyran-4-ylmethyl)piperazinehydrochloride

MS m/e (ESI) 357 (MH⁺).

1-(2-Cyclohept-1-enylphenyl)-4-propylpiperazine hydrochloride

MS m/e (ESI) 299 (MH⁺).

1-(2-Cyclohept-1-enylphenyl)-4-cyclopropylmethylpiperazine hydrochloride

MS m/e (ESI) 311 (MH⁺).

1-(2-Cyclohept-1-enylphenyl)-4-isobutylpiperazinee hydrochloride

MS m/e (ESI) 313 (MH⁺).

1-(2-Cyclohept-1-enylphenyl)-4-(tetrahydropyran-4-ylmethyl)piperazinehydrochloride

MS m/e (ESI) 355 (MH⁺).

1-(2-Cyclooct-1-enylphenyl)-4-cyclopropylmethylpiperazine hydrochloride

MS m/e (ESI) 325 (MH⁺).

1-(2-Cyclooctylphenyl)-4-cyclopropylmethylpiperazine hydrochloride

MS m/e (ESI) 327 (MH⁺).

1-Cyclopropylmethyl-4-[2-(3,3,4,4-tetramethylcyclopent-1-enyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 339 (MH⁺).

1-Butyl-4-{2-(3,3,4,4-tetramethylcyclopentyl)phenyl}piperazinehydrochloride

MS m/e (ESI) 343 (MH⁺).

1-Cyclopropylmethyl-4-{2-(3,3,4,4-tetramethylcyclopentyl)phenyl}piperazinehydrochloride

MS m/e (ESI) 341 (MH⁺).

1-Propyl-4-{2-(3,3,4,4-tetramethylcyclopent-1-enyl)phenyl}piperazinehydrochloride

MS m/e (ESI) 327 (MH⁺).

1-{2-(4-t-Butylcyclohexyl)phenyl}-4-(4,4,4-trifluorobutyl)piperazinehydrochloride

MS m/e (ESI) 411 (MH⁺).

4-{3-(4-t-Butylcyclohexyl)-4-(4-butylpiperazine-1-yl)phenyl}thiomorpholinehydrochloride

MS m/e (ESI) 458 (MH⁺).

1-Butyl-4-{2-(4-t-butylcyclohexyl)-4-(4-ethoxypiperidin-1-yl)phenyl}piperazinehydrochloride

MS m/e (ESI) 484 (MH⁺).

1-Furan-2-ylmethyl-4-(2-spiro[5.5]undec-2-en-3-ylphenyl)piperazinehydrochloride

MS m/e (ESI) 391 (MH⁺).

1-(2-Spiro[5.5]undec-2-en-3-ylphenyl)-4-(tetrahydropyran-4-ylmethyl)piperazinehydrochloride

MS m/e (ESI) 409 (MH⁺).

1-{4-(4-Methoxypiperidin-1-yl)-2-spiro[5.5]undec-2-en-3-ylphenyl}-4-propylpiperazinehydrochloride

MS m/e (ESI) 466 (MH⁺).

1-Cyclopropylmethyl-4-{4-(4-methoxypiperidin-1-yl)-2-spiro[5.5]undec-2-en-3-ylphenyl}piperazinehydrochloride

MS m/e (ESI) 478 (MH⁺).

1-{4-(4-Methoxypiperidin-1-yl)-2-spiro[5.5]undec-2-en-3-ylphenyl}-4-(3-methylbutyl)piperazinehydrochloride

MS m/e (ESI) 494 (MH⁺).

1-{4-(4-Methoxypiperidin-1-yl)-2-spiro[5.5]undec-2-en-3-ylphenyl}-4-(tetrahydropyran-4-ylmethyl)piperazinehydrochloride

MS m/e (ESI) 522 (MH⁺).

1-Cyclopentyl-4-{4-(4-methoxypiperidin-1-yl)-2-spiro[5.5]undec-2-en-3-ylphenyl}piperazinehydrochloride

MS m/e (ESI) 492 (MH⁺).

4-{4-(4-Furan-2-ylmethylpiperazin-1-yl)-3-spiro[5.5]undec-2-en-3-ylphenyl}morpholinehydrochloride

MS m/e (ESI) 476 (MH⁺).

1-(2-Spiro[5.5]undec-3-ylphenyl)-4-(tetrahydropyran-4-ylmethyl)piperazinehydrochloride

MS m/e (ESI) 411 (MH⁺).

1-{4-(4-Methoxypiperidin-1-yl)-2-spiro[5.5]undec-3-ylphenyl}-4-(3-methylbutyl)piperazinehydrochloride

MS m/e (ESI) 496 (MH⁺).

1-{4-(4-Methoxypiperidin-1-yl)-2-spiro[5.5]undec-3-ylphenyl}-4-pentylpiperazinehydrochloride

MS m/e (ESI) 496 (MH⁺).

4-{4-(4-Isobutylpiperazine-1-yl)-3-spiro[5.5]undec-3-ylphenyl}morpholinehydrochloride

MS m/e (ESI) 454 (MH⁺).

4-{4-(4-Furan-3-ylmethylpiperazin-1-yl)-3-spiro[5.5]undec-3-ylphenyl}morpholinehydrochloride

MS m/e (ESI) 478 (MH⁺).

1-{4-(4-Methoxypiperidin-1-yl)-2-spiro[2.5]oct-5-en-6-ylphenyl}-4-propylpiperazinehydrochloride

MS m/e (ESI) 424 (MH⁺).

1-Cyclopropylmethyl-4-{4-(4-methoxypiperidin-1-yl)-2-spiro[2.5]oct-5-en-6-ylphenyl}piperazinehydrochloride

MS m/e (ESI) 436 (MH⁺).

1-Isobutyl-4-{4-(4-methoxypiperidin-1-yl)-2-spiro[2.5]oct-5-en-6-ylphenyl}piperazinehydrochloride

MS m/e (ESI) 438 (MH⁺).

4-{4-(4-Butylpiperazin-1-yl)-3-spiro[2.5]oct-5-en-6-ylphenyl}morpholinehydrochloride

MS m/e (ESI) 410 (MH⁺).

1-Butyl-4-{2-(4,4-dimethylcyclohexyl)-4-(4-isopropoxypiperidin-1-yl)phenyl}piperazinehydrochloride

MS m/e (ESI) 470 (MH⁺).

4-[3-Spiro[2.5]oct-6-yl-4-{4-(tetrahydropyran-4-ylmethyl)piperazin-1-yl}phenyl]morpholinehydrochloride

MS m/e (ESI) 454 (MH⁺).

(S)-1-{2-(4,4-Diethylcyclohexyl)-4-(3-methoxypiperidin-1-yl)phenyl}-4-pentylpiperazinehydrochloride

MS m/e (ESI) 484 (MH⁺).

1-Cyclohexyl-4-{2-(3,3,5,5-tetramethylcyclohexyl)phenyl}piperazinehydrochloride

MS m/e (ESI) 383 (MH⁺).

1-Isobutyl-4-{2-(3,3,4,4-tetramethylcyclopentyl)phenyl}piperazinehydrochloride

MS m/e (ESI) 343 (MH⁺).

1-Butyl-4-[2-(4-t-butylcyclohexyl)-5-pyridin-3-yl-phenyl]piperazine

MS m/e (ESI) 434 (MH⁺).

4-[4-(4-t-Butylcyclohexyl)-3-(4-pentylpiperazin-1-yl)phenyl]morpholinehydrochloride

MS m/e (ESI) 456 (MH⁺).

4-{4-(4-t-Butylcyclohexyl)-3-[4-(3-methylbutyl)piperazin-1-yl]phenyl}morpholinehydrochloride

MS m/e (ESI) 456 (MH⁺).

[4-(4-t-Butylcyclohex-1-enyl)-3-(4-butylpiperazine-1-yl)phenyl]ethylaminehydrochloride

MS m/e (ESI) 398 (MH⁺).

4-[3-(4,4-Dimethylcyclohex-1-enyl)-4-(4-pentylpiperazin-1-yl)phenyl]morpholinehydrochloride

MS m/e (ESI) 426 (MH⁺).

4-{3-(4,4-Dimethylcyclohex-1-enyl)-4-[4-(tetrahydropyran-4-ylmethyl)piperazin-1-yl]phenyl}morpholinehydrochloride

MS m/e (ESI) 454 (MH⁺).

1-Butyl-4-[2-(4,4-dimethylcyclohex-1-enyl)-4-(4-methoxypiperidin-1-yl)phenyl]piperazinehydrochloride

MS m/e (ESI) 440 (MH⁺).

1-[2-(4,4-Dimethylcyclohex-1-enyl)-4-(4-methoxypiperidin-1-yl)phenyl]-4-propylpiperazinehydrochloride

MS m/e (ESI) 426 (MH⁺).

1-[2-(4,4-Dimethylcyclohex-1-enyl)-4-(4-methoxypiperidin-1-yl)phenyl]-4-pentylpiperazinehydrochloride

MS m/e (ESI) 454 (MH⁺).

1-[2-(4,4-Dimethylcyclohex-1-enyl)-4-(4-methoxypiperidin-1-yl)phenyl]-4-isobutylpiperazineehydrochloride

MS m/e (ESI) 440 (MH⁺).

1-[2-(4,4-Dimethylcyclohex-1-enyl)-4-(4-methoxypiperidin-1-yl)phenyl]-4-(tetrahydropyran-4-ylmethyl)piperazinehydrochloride

MS m/e (ESI) 482 (MH⁺).

1-{4-[2-(4,4-Dimethylcyclohex-1-enyl)-4-(4-methoxypiperidin-1-yl)phenyl]piperazin-1-yl}butan-2-onehydrochloride

MS m/e (ESI) 454 (MH⁺).

4-[3-(4,4-Dimethylcyclohex-1-enyl)-4-(4-furan-3-ylmethylpiperazin-1-yl)phenyl]morpholinehydrochloride

MS m/e (ESI) 436 (MH⁺).

1-[2-(4,4-Dimethylcyclohex-1-enyl)-4-(4-methoxypiperidin-1-yl)phenyl]-4-furan-3-ylmethylpiperazinehydrochloride

MS m/e (ESI) 464 (MH⁺).

1-[2-(4,4-Dimethylcyclohex-1-enyl)phenyl]-4pentylpiperazinehydrochloride

MS m/e (ESI) 341 (MH⁺).

1-Cyclopropylmethyl-4-[2-(4,4-dimethylcyclohex-1-enyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 325 (MH⁺).

1-[2-(4,4-Dimethylcyclohex-1-enyl)phenyl]-4-(tetrahydropyran-4-ylmethyl)piperazinehydrochloride

MS m/e (ESI) 369 (MH⁺).

1-[2-(4,4-Dimethylcyclohex-1-enyl)phenyl]-4-furan-2-ylmethylpiperazinehydrochloride

MS m/e (ESI) 351 (MH⁺).

1-[2-(4,4-Dimethylcyclohex-1-enyl)phenyl]-4-furan-3-ylmethylpiperazinehydrochloride

MS m/e (ESI) 351 (MH⁺).

1-[2-(4,4-Dimethylcyclohex-1-enyl)phenyl]-4-(2-methoxyethyl)piperazinehydrochloride

MS m/e (ESI) 329 (MH⁺).

1-[2-(4,4-Dimethylcyclohexyl)phenyl]-4-pentylpiperazine hydrochloride

MS m/e (ESI) 343 (MH⁺).

1-Cyclopropylmethyl-4-[2-(4,4-dimethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 327 (MH⁺).

4-[3-(4,4-Dimethylcyclohexyl)-4-(4-pentylpiperazin-1-yl)phenyl]morpholinehydrochloride

MS m/e (ESI) 428 (MH⁺).

4-[3-(4,4-Dimethylcyclohexyl)-4-(4-furan-2-ylmethylpiperazin-1-yl)phenyl]morpholinehydrochloride

MS m/e (ESI) 438 (MH⁺).

4-[3-(4,4-Dimethylcyclohexyl)-4-(4-furan-3-ylmethylpiperazin-1-yl)phenyl]morpholinehydrochloride

MS m/e (ESI) 438 (MH⁺).

1-[2-(4,4-Dimethylcyclohexyl)-4-(4-methoxypiperidin-1-yl)phenyl]-4-pentylpiperazinehydrochloride

MS m/e (ESI) 456 (MH⁺).

1-[2-(4,4-Dimethylcyclohexyl)-4-(4-methoxypiperidin-1-yl)phenyl]-4-isobutylpiperazinehydrochloride

MS m/e (ESI) 442 (MH⁺).

1-[2-(4,4-Dimethylcyclohexyl)-4-(4-methoxypiperidin-1-yl)phenyl]-4-(tetrahydropyran-4-ylmethyl)piperazinehydrochloride

MS m/e (ESI) 484 (MH⁺).

1-[2-(4,4-Dimethylcyclohexyl)-4-(4-methoxypiperidin-1-yl)phenyl]-4-furan-2-ylmethylpiperazinehydrochloride

MS m/e (ESI) 466 (MH⁺).

1-[2-(4,4-Dimethylcyclohexyl)-4-(4-methoxypiperidin-1-yl)phenyl]-4-furan-3-ylmethylpiperazinehydrochloride

MS m/e (ESI) 466 (MH⁺).

1-{4-[2-(4,4-Dimethylcyclohexyl)-4-(4-methoxypiperidin-1-yl)phenyl]piperazin-1-yl}butan-2-onehydrochloride

MS m/e (ESI) 456 (MH⁺).

1-[2-(4,4-Dimethylcyclohexyl)phenyl]-4-isobutylpiperazinee hydrochloride

MS m/e (ESI) 329 (MH⁺).

1-Cyclobutylmethyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 369 (MH⁺).

{4-[2-(3,3,5,5-Tetramethylcyclohex-1-enyl)phenyl]piperazin-1-yl}acetonitrilehydrochloride

MS m/e (ESI) 338 (MH⁺).

1-(2-Ethoxyethyl)-4-[2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 371 (MH⁺).

1-Cyclobutylmethyl-4-[2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 367 (MH⁺).

cis-4-[3-(4,4-Dimethylcyclohexyl)-4-(4-propylpiperazin-1-yl)phenyl]-2,6-dimethylmorpholinehydrochloride

MS m/e (ESI) 428 (MH⁺).

cis-4-[3-(4,4-Dimethylcyclohexyl)-4-(4-pentylpiperazin-1-yl)phenyl]-2,6-dimethylmorpholinehydrochloride

MS m/e (ESI) 456 (MH⁺).

cis-4-{3-(4,4-Dimethylcyclohexyl)-4-[4-(tetrahydropyran-4-ylmethyl)piperazin-1-yl)phenyl]-2,6-dimethylmorpholinehydrochloride

MS m/e (ESI) 484 (MH⁺).

cis-4-[3-(4,4-Dimethylcyclohexyl)-4-(4-furan-3-ylmethylpiperazin-1-yl)phenyl]-2,6-dimethylmorpholinehydrochloride

MS m/e (ESI) 466 (MH⁺).

cis-1-{4-[2-(4,4-Dimethylcyclohexyl)-4-(2,6-dimethylmorpholin-4-yl)phenyl]piperazin-1-yl}butan-2-onehydrochloride

MS m/e (ESI) 456 (MH⁺).

cis-4-{3-(4,4-Dimethylcyclohexyl)-4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl}-2,6-dimethylmorpholinehydrochloride

MS m/e (ESI) 444 (MH⁺).

cis-4-{3-(4,4-Dimethylcyclohexyl)-4-[4-(2-ethoxyethyl)piperazin-1-yl]phenyl}-2,6-dimethylmorpholinehydrochloride

MS m/e (ESI) 458 (MH⁺).

cis-4-[4-(4-Cyclobutylmethylpiperazin-1-yl)-3-(4,4-dimethylcyclohexyl)phenyl]-2,6-dimethylmorpholinehydrochloride

MS m/e (ESI) 454 (MH⁺).

1-Butyl-4-[2-(4,4-dimethylcyclohexyl)-4-pyrrolidin-1-ylphenyl]piperazinehydrochloride

MS m/e (ESI) 398 (MH⁺).

1-[3-(4,4-Dimethylcyclohexyl)-4-(4-pentylpiperazin-1-yl)phenyl]piperidine-4-carbonitrilehydrochloride

MS m/e (ESI) 451 (MH⁺).

1-[3-(4,4-Dimethylcyclohexyl)-4-(4-isobutylpiperazine-1-yl)phenyl]piperidine-4-carbonitrilehydrochloride

MS m/e (ESI) 437 (MH⁺).

4-[4-(4-Cyclobutylmethylpiperazin-1-yl)-3-(4,4-dimethylcyclohexyl)phenyl]morpholinehydrochloride

MS m/e (ESI) 426 (MH⁺).

1-Cyclobutylmethyl-4-[2-(4,4-dimethylcyclohexyl)-4-(4-methoxypiperidin-1-yl)phenyl]piperazinehydrochloride

MS m/e (ESI) 454 (MH⁺).

1-[2-(4,4-Dimethylcyclohexyl-4-piperidin-1-ylphenyl]-4-propylpiperazinehydrochloride

MS m/e (ESI) 398 (MH⁺).

1-[2-(4,4-Dimethylcyclohexyl)-4-piperidin-1-ylphenyl]-4-(tetrahydropyran-4-ylmethyl)piperazinehydrochloride

MS m/e (ESI) 454 (MH⁺).

1-{4-[2-(4,4-Dimethylcyclohexyl)-4-piperidin-1-ylphenyl]piperazin-1-yl}butan-2-onehydrochloride

MS m/e (ESI) 426 (MH⁺).

1-[2-(4,4-Dimethylcyclohexyl)-4-piperidin-1-ylphenyl]-4-(2-methoxyethyl)piperazinehydrochloride

MS m/e (ESI) 414 (MH⁺).

1-[2-(4,4-Dimethylcyclohexyl)-4-piperidin-1-ylphenyl]-4-(2-ethoxyethyl)piperazinehydrochloride

MS m/e (ESI) 428 (MH⁺).

1-[2-(4,4-Dimethylcyclohexyl)-4-pyrrolidin-1-ylphenyl]-4-propylpiperazinehydrochloride

MS m/e (ESI) 384 (MH⁺).

1-Cyclopropylmethyl-4-[2-(4,4-dimethylcyclohexyl)-4-pyrrolidin-1-ylphenyl]piperazinehydrochloride

MS m/e (ESI) 396 (MH⁺).

1-{4-[2-(4,4-Dimethylcyclohexyl)-4-pyrrolidin-1-ylphenyl]piperazin-1-yl}butan-2-onehydrochloride

MS m/e (ESI) 412 (MH⁺).

1-[2-(4,4-Dimethylcyclohexyl)-4-pyrrolidin-1-ylphenyl]-4-(2-methoxyethyl)piperazinehydrochloride

MS m/e (ESI) 400 (MH⁺).

1-[2-(4,4-Dimethylcyclohexyl)-4-pyrrolidin-1-ylphenyl]-4-(2-ethoxyethyl)piperazinehydrochloride

MS m/e (ESI) 414 (MH⁺).

1-[4-(4-Cyclobutylmethylpiperazin-1-yl)-3-(4,4-dimethylcyclohexyl)phenyl]piperidine-4-carbonitrilehydrochloride

MS m/e (ESI) 449 (MH⁴).

N-(2-{4-[2-(4-t-Butylcyclohexyl)phenyl]piperazin-1-yl}ethyl)acetamidehydrochloride

MS m/e (ESI) 386 (MH⁺).

1-Butyl-4-[2-(4-t-butylcyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)phenyl]piperazine

MS m/e (ESI) 452 (MH⁺).

1-Butyl-4-[2-(4-t-butylcyclohexyl)-5-methylphenyl]piperazinehydrochloride

MS m/e (ESI) 371 (MH⁺).

4-[4-(4-t-Butylcyclohexyl)-3-(4-propylpiperazin-1-yl)phenyl]morpholinehydrochloride

MS m/e (ESI) 428 (MH⁺).

4-[4-(4-t-Butylcyclohexyl)-3-(4-cyclopropylmethylpiperazin-1-yl)phenyl]morpholinehydrochloride

MS m/e (ESI) 440 (MH⁺).

4-[4-(4-t-Butylcyclohexyl)-3-[4-(2-methoxyethyl)piperazin-1-yl]phenyl]morpholinehydrochloride

MS m/e (ESI) 444 (MH⁺).

[4-(4-t-Butylcyclohexyl)-3-(4-butylpiperazine-1-yl)phenyl]ethylaminehydrochloride

MS m/e (ESI) 400 (MH⁺).

1-Butyl-4-[2-(4-t-butylcyclohexyl)-5-piperidin-1-ylphenyl]piperazinehydrochloride

MS m/e (ESI) 440 (MH⁺).

4-[4-(4-Cyclopropylmethylpiperazin-1-yl)-3-(4,4-dimethylcyclohex-1-enyl)phenyl]morpholinehydrochloride

MS m/e (ESI) 410 (MH⁺).

1-Cyclopropylmethyl-4-[2-(4,4-dimethylcyclohex-1-enyl)-4-(4-methoxypiperidin-1-yl)phenyl]piperazinehydrochloride

MS m/e (ESI) 438 (MH⁺).

1-[2-(4,4-Dimethylcyclohex-1-enyl)-4-(4-methoxypiperidin-1-yl)phenyl]-4-(2-methoxyethyl)piperazinehydrochloride

MS m/e (ESI) 442 (MH⁺).

4-[3-(4,4-Dimethylcyclohex-1-enyl)-4-(4-furan-2-ylmethylpiperazin-1-yl)phenyl]morpholinehydrochloride

MS m/e (ESI) 436 (MH⁺).

1-[2-(4,4-Dimethylcyclohex-1-enyl)-4-(4-methoxypiperidin-1-yl)phenyl]-4-furan-2-ylmethylpiperazinehydrochloride

MS m/e (ESI) 464 (MH⁺).

1-[2-(4,4-Dimethylcyclohex-1-enyl)phenyl]-4-(tetrahydropyran-4-yl)piperazinehydrochloride

MS m/e (ESI) 355 (MH⁺).

1-[2-(4,4-Dimethylcyclohexyl)phenyl]-4-(tetrahydropyran-4-yl)piperazinehydrochloride

MS m/e (ESI) 357 (MH⁺).

4-{3-(4,4-Dimethylcyclohexyl)-4-[4-(tetrahydropyran-4-ylmethyl)piperazin-1-yl]phenyl}morpholinehydrochloride

MS m/e (ESI) 456 (MH⁺).

1-{4-[2-(4,4-Dimethylcyclohexyl)-4-morpholin-4-ylphenyl]piperazin-1-yl}butan-2-onehydrochloride

MS m/e (ESI) 428 (MH⁺).

1-[2-(4,4-Dimethylcyclohexyl)-4-(4-methoxypiperidin-1-yl)phenyl]-4-propylpiperazinehydrochloride

MS m/e (ESI) 428 (MH⁺).

1-Cyclopropylmethyl-4-[2-(4,4-dimethylcyclohexyl)-4-(4-methoxypiperidin1-yl)phenyl]piperazine hydrochloride

MS m/e (ESI) 440 (MH⁺).

cis-4-[3-(4,4-Dimethylcyclohexyl)-4-(4-isobutylpiperazine-1-yl)phenyl]-2,6-dimethylmorpholinehydrochloride

MS m/e (ESI) 442 (MH⁺).

cis-4-[4-(4-Cyclopropylmethylpiperazin-1-yl)-3-(4,4-dimethylcyclohexyl)phenyl]-2,6-dimethylmorpholinehydrochloride

MS m/e (ESI) 440 (MH⁺).

cis-4-[3-(4,4-Dimethylcyclohexyl)-4-(4-furan-2-ylmethylpiperazin-1-yl)phenyl]-2,6-dimethylmorpholinehydrochloride

MS m/e (ESI) 466 (MH⁺).

cis-{4-[2-(4,4-Dimethylcyclohexyl)-4-(2,6-dimethylmorpholin-4-yl)phenyl]piperazin-1-yl}acetonitrilehydrochloride

MS m/e (ESI) 425 (MH⁺).

1-[3-(4,4-Dimethylcyclohexyl)-4-(4-propylpiperazin-1-yl)phenyl]piperidine-4-carbonitrilehydrochloride

MS m/e (ESI) 423 (MH⁺).

1-[4-(4-Cyclopropylmethylpiperazin-1-yl)-3-(4,4-dimethylcyclohexyl)phenyl]piperidine-4-carbonitrilehydrochloride

MS m/e (ESI) 435 (MH⁺).

1-[3-(4,4-Dimethylcyclohexyl)-4-(4-furan-3-ylmethylpiperazin-1-yl)phenyl]piperidine-4-carbonitrilehydrochloride

MS m/e (ESI) 461 (MH⁺).

4-{3-(4,4-Dimethylcyclohexyl)-4-[4-(2-ethoxyethyl)piperazin-1-yl]phenyl}morpholinehydrochloride

MS m/e (ESI) 430 (MH⁺).

{4-[2-(4,4-Dimethylcyclohexyl)-4-(4-methoxypiperidin-1-yl)phenyl]piperazin-1-yl}acetonitrilehydrochloride

MS m/e (ESI) 425 (MH⁺).

1-[2-(4,4-Dimethylcyclohexyl)-4-piperidin-1-ylphenyl]-4-pentylpiperazinehydrochloride

MS m/e (ESI) 426 (MH⁺).

1-[2-(4,4-Dimethylcyclohexyl)-4-piperidin-1-ylphenyl]-4-isobutylpiperazineehydrochloride

MS m/e (ESI) 412 (MH⁺).

1-[2-(4,4-Dimethylcyclohexyl)-4-piperidin-1-ylphenyl]-4-furan-2-ylmethylpiperazinehydrochloride

MS m/e (ESI) 436 (MH⁺).

1-[2-(4,4-Dimethylcyclohexyl)-4-piperidin-1-ylphenyl]-4-furan-3-ylmethylpiperazinehydrochloride

MS m/e (ESI) 436 (MH⁺).

{4-[2-(4,4-Dimethylcyclohexyl)-4-piperidin-1-ylphenyl]piperazin-1-yl}acetonitrilehydrochloride

MS m/e (ESI) 395 (MH⁺).

1-Cyclobutylmethyl-4-[2-(4,4-dimethylcyclohexyl)-4-piperidin-1-ylphenyl]piperazinehydrochloride

MS m/e (ESI) 424 (MH⁺).

1-[2-(4,4-Dimethylcyclohexyl)-4-pyrrolidin-1-ylphenyl]-4-pentylpiperazinehydrochloride

MS m/e (ESI) 412 (MH⁺).

1-[2-(4,4-Dimethylcyclohexyl)-4-pyrrolidin-1-ylphenyl]-4-isobutylpiperazineehydrochloride

MS m/e (ESI) 398 (MH⁺).

1-[2-(4,4-Dimethylcyclohexyl)-4-pyrrolidin-1-ylphenyl]-4-furan-2-ylmethylpiperazinehydrochloride

MS m/e (ESI) 422 (MH⁺).

{4-[2-(4,4-Dimethylcyclohexyl)-4-pyrrolidin-1-ylphenyl]piperazin-1-yl}acetonitrilehydrochloride

MS m/e (ESI) 381 (MH⁺).

1-Cyclobutylmethyl-4-[2-(4,4-dimethylcyclohexyl)-4-pyrrolidin-1-ylphenyl]piperazinehydrochloride

MS m/e (ESI) 410 (MH⁺).

1-Butyl-4-[4-methyl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 371 (MH⁺).

1-Cyclopropylmethyl-4-[4-methyl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 369 (MH⁺).

1-[2-Methyl-6-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-propylpiperazinehydrochloride

MS m/e (ESI) 357 (MH⁺).

1-Butyl-4-[2-methyl-6-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 371 (MH⁺).

1-Cyclopropylmethyl-4-[2-methyl-6-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 369 (MH⁺).

1-[2-Methyl-6-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]-4-propylpiperazinehydrochloride

MS m/e (ESI) 355 (MH⁺).

1-Butyl-4-[2-methyl-6-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 369 (MH⁺).

1-Cyclopropylmethyl-4-[2-methyl-6-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 367 (MH⁺).

1-Butyl-4-[5-methyl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 371 (MH⁺).

1-[5-Methyl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-propylpiperazinehydrochloride

MS m/e (ESI) 357 (MH⁺).

1-Cyclopropylmethyl-4-[5-methyl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 369 (MH⁺).

1-Butyl-4-[3-methyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 369 (MH⁺).

1-Cyclopropylmethyl-4-[3-methyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 367 (MH⁺).

1-Cyclopropylmethyl-4-[5-methoxy-4-piperidin-1-yl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 468 (MH⁺).

1-[5-Methyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]-4-propylpiperazinehydrochloride

MS m/e (ESI) 355 (MH⁺).

1-Butyl-4-[5-methyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 369 (MH⁺).

1-Cyclopropylmethyl-4-[5-methyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 367 (MH⁺).

1-[4-Methyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]-4-propylpiperazinehydrochloride

MS m/e (ESI) 355 (MH⁺).

1-Butyl-4-[4-methyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 369 (MH⁺).

1-Cyclopropylmethyl-4-[4-methyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 367 (MH⁺).

1-[5-Furan-3-yl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-propylpiperazinehydrochloride

MS m/e (ESI) 409 (MH⁺).

1-Cyclopropylmethyl-4-[5-furan-3-yl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 421 (MH⁺).

1-[5-Furan-2-yl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-propylpiperazinehydrochloride

MS m/e (ESI) 409 (MH⁺).

4-[3-(4-Propylpiperazin-1-yl)-4-(3,3,5,5-tetramethylcyclohexyl)phenyl]morpholinehydrochloride

MS m/e (ESI) 428 (MH⁺).

4-[3-(4-Cyclopropylmethylpiperazin-1-yl)-4-(3,3,5,5-tetramethylcyclohexyl)phenyl]morpholinehydrochloride

MS m/e (ESI) 440 (MH⁺).

Dimethyl[3-(4-propylpiperazin-1-yl)-4-(3,3,5,5-tetramethylcyclohexyl)phenyl]aminehydrochloride

MS m/e (ESI) 386 (MH⁺).

[3-(4-Butylpiperazin-1-yl)-4-(3,3,5,5-tetramethylcyclohexyl)phenyl]dimethylaminehydrochloride

MS m/e (ESI) 400 (MH⁺).

[3-(4-Cyclopropylmethylpiperazin-1-yl)-4-(3,3,5,5-tetramethylcyclohexyl)phenyl]dimethylaminehydrochloride

MS m/e (ESI) 398 (MH⁺).

1-[3-(4-Butylpiperazin-1-yl)-4-(3,3,5,5-tetramethylcyclohexyl)phenyl]ethanonehydrochloride

MS m/e (ESI) 399 (MH⁺).

1-[3-(4-Cyclopropylmethylpiperazin-1-yl)-4-(3,3,5,5-tetramethylcyclohexyl)phenyl]ethanonehydrochloride

MS m/e (ESI) 397 (MH⁺).

1-[2-(4-t-Butylcyclohexyl)phenyl]-4-pentylpiperazine hydrochloride

MS m/e (ESI) 371 (MH⁺).

1-Butyl-4-[2-(4,4-diethylcyclohex-1-enyl)phenyl]piperazine hydrochloride

MS m/e (ESI) 355 (MH⁺).

1-Butyl-4-(2-spiro[5.5]undec-2-en-3-ylphenyl)piperazine hydrochloride

MS m/e (ESI) 367 (MH⁺).

1-Butyl-4-(2-spiro[5.5]undec-3-ylphenyl)piperazine hydrochloride

MS m/e (ESI) 369 (MH⁺).

1-[2-(4,4-Diethylcyclohex-1-enyl)phenyl]-4-propylpiperazinehydrochloride

MS m/e (ESI) 341 (MH⁺).

1-[2-(4,4-Diethylcyclohex-1-enyl)phenyl]-4-isobutylpiperazineehydrochloride

MS m/e (ESI) 355 (MH⁺).

1-[2-(4,4-Diethylcyclohex-1-enyl)phenyl]-4-(3-methylbutyl)piperazinehydrochloride

MS m/e (ESI) 369 (MH⁺).

1-Cyclopropylmethyl-4-[2-(4,4-diethylcyclohex-1-enyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 353 (MH⁺).

1-[2-(4,4-Diethylcyclohexyl)phenyl]-4-isobutylpiperazinee hydrochloride

MS m/e (ESI) 357 (MH⁺).

1-{4-[2-(4,4-Diethylcyclohex-1-enyl)phenyl]piperazin-1-yl}butan-1-one

MS m/e (ESI) 369 (MH⁺).

1-{4-[2-(4,4-Diethylcyclohex-1-enyl)phenyl]piperazin-1-yl}butan-2-onehydrochloride

MS m/e (ESI) 369 (MH⁺).

1-[2-(4,4-Diethylcyclohex-1-enyl)phenyl]-4-(2-methoxyethyl)piperazinehydrochloride

MS m/e (ESI) 357 (MH⁺).

1-[2-(4,4-Diethylcyclohexyl)phenyl]-4-(2-methoxyethyl)piperazinehydrochloride

MS m/e (ESI) 359 (MH⁺).

1-[2-(4,4-Diethylcyclohex-1-enyl)phenyl]-4-(tetrahydropyran-4-ylmethyl)piperazinehydrochloride

MS m/e (ESI) 397 (MH⁺).

1-[2-(4,4-Diethylcyclohexyl)phenyl]-4-(tetrahydropyran-4-ylmethyl)piperazinehydrochloride

MS m/e (ESI) 399 (MH⁺).

4-[4-(4-Butylpiperazin-1-yl)-3-(4,4-diethylcyclohex-1-enyl)phenyl]morpholinehydrochloride

MS m/e (ESI) 440 (MH⁺).

4-[4-(4-Cyclopropylmethylpiperazin-1-yl)-3-(4,4-diethylcyclohex-1-enyl)phenyl]morpholinehydrochloride

MS m/e (ESI) 438 (MH⁺).

4-{3-(4,4-Diethylcyclohex-1-enyl)-4-[4-(tetrahydropyran-4-ylmethyl)piperazin-1-yl]phenyl}morpholinehydrochloride

MS m/e (ESI) 482 (MH⁺).

4-{3-(4,4-Diethylcyclohex-1-enyl)-4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl}morpholinehydrochloride

MS m/e (ESI) 442 (MH⁺).

4-[3-(4,4-Diethylcyclohexyl)-4-(4-propylpiperazin-1-yl)phenyl]morpholinehydrochloride

MS m/e (ESI) 428 (MH⁺).

4-[3-(4,4-Diethylcyclohexyl)-4-(4-isobutylpiperazine-1-yl]phenyl]morpholinehydrochloride

MS m/e (ESI) 442 (MH⁺).

4-[3-(4,4-Diethylcyclohexyl)-4-(4-pentylpiperazin-1-yl)phenyl]morpholinehydrochloride

MS m/e (ESI) 456 (MH⁺).

4-[4-(4-Cyclopropylmethylpiperazin-1-yl)-3-(4,4-dimethylcyclohexyl)phenyl]morpholinehydrochloride

MS m/e (ESI) 440 (MH⁺).

4-{3-(4,4-Diethylcyclohexyl)-4-[4-(tetrahydropyran-4-ylmethyl)piperazin-1-yl]phenyl}morpholinehydrochloride

MS m/e (ESI) 484 (MH⁺).

1-Butyl-4-[2-(4,4-diethylcyclohex-1-enyl)-4-(4-methoxypiperidin-1-yl)phenyl]piperazinehydrochloride

MS m/e (ESI) 468 (MH⁺).

1-[2-(4,4-Diethylcyclohex-1-enyl)-4-(4-methoxypiperidin-1-yl)phenyl]-4-isobutylpiperazineehydrochloride

MS m/e (ESI) 468 (MH⁺).

1-[2-(4,4-Diethylcyclohex-1-enyl)-4-(4-methoxypiperidin-1-yl)phenyl]-4-pentylpiperazinehydrochloride

MS m/e (ESI) 482 (MH⁺).

1-Cyclopropylmethyl-4-[2-(4,4-diethylcyclohex-1-enyl)-4-(4-methoxypiperidin-1-yl)phenyl]piperazinehydrochloride

MS m/e (ESI) 466 (MH⁺).

1-[2-(4,4-Diethylcyclohex-1-enyl)-4-(4-methoxypiperidin-1-yl)phenyl]-4-(tetrahydropyran-4-ylmethyl)piperazinehydrochloride

MS m/e (ESI) 510 (MH⁺).

1-Butyl-4-[2-(4,4-dimethylcyclohexyl)-4-(4-methoxypiperidin-1-yl)phenyl]piperazinehydrochloride

MS m/e (ESI) 470 (MH⁺).

1-[2-(4,4-Diethylcyclohexyl)-4-(4-methoxypiperidin-1-yl)phenyl]-4-propylpiperazinehydrochloride

MS m/e (ESI) 456 (MH⁺).

1-[2-(4,4-Diethylcyclohexyl)-4-(4-methoxypiperidin-1-yl)phenyl]-4-isobutylpiperazineehydrochloride

MS m/e (ESI) 470 (MH⁺).

1-[2-(4,4-Diethylcyclohexyl)-4-(4-methoxypiperidin-1-yl)phenyl]-4-(tetrahydropyran-4-ylmethylpiperazinehydrochloride

MS m/e (ESI) 512 (MH⁺).

1-{4-[2-(4,4-Diethylcyclohex-1-enyl)-4-(4-methoxypiperidin-1-yl)phenyl]piperazin-1-yl}butan-2-onehydrochloride

MS m/e (ESI) 482 (MH⁺).

1-[2-(4,4-Diethylcyclohex-1-enyl)-4-(4-methoxypiperidin-1-yl)phenyl]-4-(2-methoxyethyl)piperazinehydrochloride

MS m/e (ESI) 470 (MH⁺).

1-{4-[2-(4,4-Diethylcyclohexyl)-4-(4-methoxypiperidin-1-yl)phenyl]piperazin-1-yl}butan-2-onehydrochloride

MS m/e (ESI) 484 (MH⁺).

1-[2-(4,4-Diethylcyclohexyl)-4-(4-methoxypiperidin-1-yl)phenyl]-4-(2-methoxyethyl)piperazinehydrochloride

MS m/e (ESI) 472 (MH⁺).

4-[3-(4,4-Diethylcyclohex-1-enyl)-4-(4-furan-2-ylmethylpiperazin-1-yl)phenyl]morpholinehydrochloride

MS m/e (ESI) 464 (MH⁺).

4-[3-(4,4-Diethylcyclohex-1-enyl)-4-(4-furan-3-ylmethylpiperazin-1-yl)phenyl]morpholinehydrochloride

MS m/e (ESI) 464 (MH⁺).

4-[3-(4,4-Diethylcyclohexyl)-4-(4-furan-2-ylmethylpiperazin-1-yl)phenyl]morpholinehydrochloride

MS m/e (ESI) 466 (MH⁺).

4-[3-(4,4-Diethylcyclohexyl)-4-(4-furan-3-ylmethylpiperazin-1-yl)phenyl]morpholinehydrochloride

MS m/e (ESI) 466 (MH⁺).

1-[2-(4,4-Diethylcyclohex-1-enyl)-4-(4-methoxypiperidin-1-yl)phenyl]-4-furan-2-ylmethylpiperazinehydrochloride

MS m/e (ESI) 492 (MH⁺).

1-[2-(4,4-Diethylcyclohex-1-enyl)-4-(4-methoxypiperidin-1-yl)phenyl]-4-furan-3-ylmethylpiperazinehydrochloride

MS m/e (ESI) 492 (MH⁺).

1-[2-(4,4-Diethylcyclohexyl)-4-(4-methoxypiperidin-1-yl)phenyl]-4-furan-2-ylmethylpiperazinehydrochloride

MS m/e (ESI) 494 (MH⁺).

1-[2-(4,4-Diethylcyclohexyl)-4-(4-methoxypiperidin-1-yl)phenyl]-4-furan-3-ylmethylpiperazinehydrochloride

MS m/e (ESI) 494 (MH⁺).

1-[2-(4,4-Diethylcyclohex-1-enyl)phenyl]-4-furan-2-ylmethylpiperazinehydrochloride

MS m/e (ESI) 379 (MH⁺).

1-[2-(4,4-Diethylcyclohex-1-enyl)phenyl]-4-furan-3-ylmethylpiperazinehydrochloride

MS m/e (ESI) 379 (MH⁺).

{4-[2-(4,4-Diethylcyclohex-1-enyl)phenyl]piperazin-1-yl}morpholin-4-ylmethanone

MS m/e (ESI) 412 (MH⁺).

1-[2-(4,4-Diethylcyclohexyl)phenyl]-4-furan-2-ylmethylpiperazinehydrochloride

MS m/e (ESI) 381 (MH⁺).

1-[2-(4,4-Diethylcyclohexyl)phenyl]-4-furan-3-ylmethylpiperazinehydrochloride

MS m/e (ESI) 381 (MH⁺).

{4-[2-(4,4-Diethylcyclohex-1-enyl)phenyl]piperazin-1-yl}piperidin-1-ylmethanone

MS m/e (ESI) 410 (MH⁺).

{4-[2-(4,4-Diethylcyclohexyl)phenyl]piperazin-1-yl}piperidin-1-ylmethanone

MS m/e (ESI) 412 (MH⁺).

1-[2-(4,4-Diethylcyclohexyl)phenyl]-4-pentylpiperazine hydrochloride

MS m/e (ESI) 371 (MH⁺).

cis-4-[4-(4-Butylpiperazin-1-yl)-3-(4,4-dimethylcyclohexyl)phenyl]-2,6-dimethylmorpholinehydrochloride

MS m/e (ESI) 470 (MH⁺).

cis-4-[3-(4,4-Diethylcyclohexyl)-4-(4-pentylpiperazin-1-yl)phenyl]-2,6-dimethylmorpholinehydrochloride

MS m/e (ESI) 484 (MH⁺).

cis-4-[4-(4-Cyclopropylmethylpiperazin-1-yl)-3-(4,4-dimethylcyclohexyl)phenyl]-2,6-dimethylmorpholinehydrochloride

MS m/e (ESI) 468 (MH⁺).

1-[4-Methoxy-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-propylpiperazinehydrochloride

MS m/e (ESI) 373 (MH⁺).

1-[4-Methoxy-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-pentylpiperazinehydrochloride

MS m/e (ESI) 401 (MH⁺).

1-Isobutyl-4-[4-methoxy-2-(3,355-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 387 (MH⁺).

1-Cyclopropylmethyl-4-[4-methoxy-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 385 (MH⁺).

1-[4,5-Dimethoxy-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-propylpiperazinehydrochloride

MS m/e (ESI) 403 (MH⁺).

1-Butyl-4-[4,5-dimethoxy-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 417 (MH⁺).

1-[4,5-Dimethoxy-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-pentylpiperazinehydrochloride

MS m/e (ESI) 431 (MH⁺).

1-[4,5-Dimethoxy-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-(tetrahydropyran-4-ylmethyl)piperazinehydrochloride

MS m/e (ESI) 459 (MH⁺).

1-Cycloheptyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 397 (MH⁺).

1-(4-Methylcyclohexyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 397 (MH⁺).

1-(1-Ethylpropyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 371 (MH⁺).

1-(Tetrahydrothiopyran-4-yl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 401 (MH⁺).

cis-4-[3-(4,4-Diethylcyclohexyl)-4-(4-propylpiperazin-1-yl)phenyl]-2,6-dimethylmorpholinehydrochloride

MS m/e (ESI) 456 (MH⁺).

4-[5-(4,4-Diethylcyclohexyl)-2-methoxy-4-(4-pentylpiperazin-1-yl)phenyl]morpholinehydrochloride

MS m/e (ESI) 486 (MH⁺).

4-(4-Propylpiperazin-1-yl)-3-(3,3,5,5-tetramethylcyclohexyl)benzonitrilehydrochloride

MS m/e (ESI) 368 (MH⁺).

1-[3-Fluoro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]-4-propylpiperazinehydrochloride

MS m/e (ESI) 359 (MH⁺).

trans-2-{4-[2-(3,3,5,5-Ttramethylcyclohexyl)phenyl]piperazin-1-ylmethyl}cyclopropanecarboxylicacid dimethylamide hydrochloride

MS m/e (ESI) 426 (MH⁺).

1-{4-[2-(4-t-Butylcyclohexyl)phenyl]piperazin-1-yl}butan-2-onehydrochloride

MS m/e (ESI) 371 (MH⁺).

1-{4-[2-(4-t-Butylcyclohexyl)phenyl]piperazin-1-yl}butan-2-olhydrochloride

MS m/e (ESI) 373 (MH⁺).

trans-4-Butyl-1-[2-(4-t-butylcyclohexyl)phenyl]piperazin-2-onehydrochloride

MS m/e (ESI) 371 (MH⁺).

cis-4-Butyl-1-[2-(4-t-butylcyclohexyl)phenyl]piperazin-2-onehydrochloride

MS m/e (ESI) 371 (MH⁺).

2-{4-[2-(4-t-Butylcyclohexyl)phenyl]piperazin-1-yl}acetamidehydrochloride

MS m/e (ESI) 358 (MH⁺).

4-(4-t-Butylcyclohexyl)-3-(4-butylpiperazine-1-yl)benzonitrilehydrochloride

MS m/e (ESI) 382 (MH⁺).

2-{4-[2-(4-t-Butylcyclohexyl)phenyl]piperazin-1-yl}-N-cyclopropylacetamidehydrochloride

MS m/e (ESI) 398 (MH⁺).

2-{4-[2-(4-t-Butylcyclohexyl)phenyl]piperazin-1-yl}-1-piperidin-1-ylpropan-1-onehydrochloride

MS m/e (ESI) 440 (MH⁺).

2-{4-[2-(4-t-Butylcyclohexyl)phenyl]piperazin-1-yl}-N-methylacetamidehydrochloride

MS m/e (ESI) 372 (MH⁺).

3-{4-[2-(4-t-Butylcyclohexyl)phenyl]piperazin-1-yl}pyrrolidin-2-onehydrochloride

MS m/e (ESI) 384 (MH⁺).

2-{4-[2-(4-t-Butylcyclohexyl)phenyl]piperazin-1-yl}-N-isopropylacetamidehydrochloride

MS m/e (ESI) 400 (MH⁺).

2-{4-[2-(4-t-Butylcyclohexyl)phenyl]piperazin-1-yl}-N-ethyl-N-methylacetamidehydrochloride

MS m/e (ESI) 400 (MH⁺).

2-{4-[2-(4-t-Butylcyclohexyl)phenyl]piperazin-1-yl}-N,N-diethylacetamidehydrochloride

MS m/e (ESI) 414 (MH⁺).

2-{4-[2-(4-t-Butylcyclohexyl)phenyl]piperazin-1-yl}-N-(2-methoxyethyl)acetamidehydrochloride

MS m/e (ESI) 416 (MH⁺).

1-[2-(4-t-Butylcyclohexyl)phenyl]-4-methylpiperazine hydrochloride

MS m/e (ESI) 315 (MH⁺).

1-[2-(4-t-Butylcyclohexyl)phenyl]-4-ethylpiperazine hydrochloride

MS m/e (ESI) 329 (MH⁺).

1-[2-(4-t-Butylcyclohex-1-enyl)phenyl]-4-ethylpiperazine hydrochloride

MS m/e (ESI) 327 (MH⁺).

1-[2-(4-t-Butylcyclohex-1-enyl)phenyl]-4-cyclopropylmethylpiperazinehydrochloride

MS m/e (ESI) 353 (MH⁺).

N-Butyl-2-{4-[2-(4-t-butylcyclohexyl)phenyl]piperazin-1-yl}acetamidehydrochloride

MS m/e (ESI) 414 (MH⁺).

1-Azocan-1-yl-2-{4-[2-(4-t-butylcyclohexyl)phenyl]piperazin-1-yl}ethanonehydrochloride

MS m/e (ESI) 454 (MH⁺).

[3-(4-t-Butylcyclohexyl)-4-(4-butylpiperazine-1-yl)phenyl]methylaminehydrochloride

MS m/e (ESI) 386 (MH⁺).

[3-(4-t-Butylcyclohexyl)-4-(4-butylpiperazine-1-yl)phenyl]dimethylaminehydrochloride

MS m/e (ESI) 400 (MH⁺).

1-Butyl-4-[2-(4-t-butylcyclohexyl)-4-pyridin-3-ylphenyl]piperazinedihydrochloride

MS m/e (ESI) 434 (MH⁺).

[3-(4-t-Butylcyclohex-1-enyl)-4-(4-butylpiperazine-1-yl)phenyl]dimethylaminehydrochloride

MS m/e (ESI) 398 (MH⁺).

1-Propyl-4-[2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 341 (MH⁺).

1-(Tetrahydropyran-4-ylmethyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 399 (MH⁺).

1-Butyl-4-[4-(4-methoxypiperidin-1-yl)-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 468 (MH⁺).

1-Cyclopropylmethyl-4-[4-(4-methoxypiperidin-1-yl)-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 466 (MH⁺).

1-[4-(4-Methoxypiperidin-1-yl)-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]-4-(tetrahydropyran-4-ylmethyl)piperazinehydrochloride

MS m/e (ESI) 510 (MH⁺).

1-Furan-3-ylmethyl-4-[4-(4-methoxypiperidin-1-yl)-2-(3,355-tetramethylcyclohex-1-enyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 492 (MH⁺).

1-{4-[4-(4-Methoxypiperidin-1-yl)-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazin-1-yl}butan-2-onehydrochloride

MS m/e (ESI) 482 (MH⁺).

1-(2-Methoxyethyl)-4-[4-(4-methoxypiperidin-1-yl)-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 470 (MH⁺).

1-[4-(4-Methoxypiperidin-1-yl)-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-propylpiperazinehydrochloride

MS m/e (ESI) 456 (MH⁺).

1-Cyclopropylmethyl-4-[4-(4-methoxypiperidin-1-yl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 468 (MH⁺).

1-[4-(4-Methoxypiperidin-1-yl)-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-(tetrahydropyran-4-ylmethyl)piperazinehydrochloride

MS m/e (ESI) 512 (MH⁺).

1-{4-[4-(4-Methoxypiperidin-1-yl)-2-(3,3,5,5-tetramethylcyclohexylphenyl]piperazin-1-yl}butan-2-onehydrochloride

MS m/e (ESI) 484 (MH⁺).

1-(2-Methoxyethyl)-4-[4-(4-methoxypiperidin-1-yl)-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 472 (MH⁺).

4-[4-(4-Butylpiperazin-1-yl)-3-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]morpholinehydrochloride

MS m/e (ESI) 440 (MH⁺).

4-[4-(4-Pentylpiperazin-1-yl)-3-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]morpholinehydrochloride

MS m/e (ESI) 454 (MH⁺).

4-[4-(4-Cyclopropylmethylpiperazin-1-yl)-3-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]morpholinehydrochloride

MS m/e (ESI) 438 (MH⁺).

4-{4-[4-(Tetrahydropyran-4-ylmethyl)piperazin-1-yl]-3-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl}morpholinehydrochloride

MS m/e (ESI) 482 (MH⁺).

4-[4-(4-Furan-3-ylmethylpiperazin-1-yl)-3-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]morpholinehydrochloride

MS m/e (ESI) 464 (MH⁺).

1-{4-[4-Morpholin-4-yl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazin-1-yl}butan-2-onehydrochloride

MS m/e (ESI) 454 (MH⁺).

4-[4-(4-Butylpiperazin-1-yl)-3-(3,3,5,5-tetramethylcyclohexyl)phenyl]morpholinehydrochloride

MS m/e (ESI) 442 (MH⁺).

4-[4-(4-Pentylpiperazin-1-yl)-3-(3,3,5,5-tetramethylcyclohexyl)phenyl]morpholinehydrochloride

MS m/e (ESI) 456 (MH⁺).

4-[4-(4-Cyclopropylmethylpiperazin-1-yl)-3-(3,3,5,5-tetramethylcyclohexyl)phenyl]morpholinehydrochloride

MS m/e (ESI) 440 (MH⁺).

4-{4-[4-(Tetrahydropyran-4-ylmethyl)piperazin-1-yl]-3-(3,3,5,5-tetramethylcyclohexyl)phenyl}morpholinehydrochloride

MS m/e (ESI) 484 (MH⁺).

4-[4-(4-Furan-3-ylmethylpiperazin-1-yl)-3-(3,3,5,5-tetramethylcyclohexyl)phenyl]morpholinehydrochloride

MS m/e (ESI) 466 (MH⁺).

1-{4-[4-Morpholin-4-yl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazin-1-yl}butan-2-onehydrochloride

MS m/e (ESI) 456 (MH⁺).

4-{4-[4-(2-Methoxyethyl)piperazin-1-yl]-3-(3.3,5,5-tetramethylcyclohexyl)phenyl}morpholine hydrochloride

MS m/e (ESI) 444 (MH⁺).

1-[4-(4-Ethoxypiperidin-1-yl)-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-propylpiperazinehydrochloride

MS m/e (ESI) 470 (MH⁺).

1-{4-[4-(4-Ethoxypiperidin-1-yl)-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazin-1-yl}butan-2-onehydrochloride

MS m/e (ESI) 498 (MH⁺).

2-{4-[4-(4-Methoxypiperidin-1-yl)-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazin-1-yl}-N-methylacetamidehydrochloride

MS m/e (ESI) 485 (MH⁺).

(R)-1-[4-(3-Methoxypyrrolidin-1-yl)-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-propylpiperazinehydrochloride

MS m/e (ESI) 442 (MH⁺).

(R)-1-Butyl-4-[4-(3-methoxypyrrolidin-1-yl)-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 456 (MH⁺).

(R)-1-Cyclopropylmethyl-4-[4-(3-methoxypyrrolidin-1-yl)-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 454 (MH⁺).

cis-2,6-Dimethyl-4-[4-(4-propylpiperazin-1-yl)-3-(3,3,5,5-tetramethylcyclohexyl)phenyl]morpholinehydrochloride

MS m/e (ESI) 456 (MH⁺).

cis-4-[4-(4-Cyclopropylmethylpiperazin-1-yl)-3-(3,3,5,5-tetramethylcyclohexyl)phenyl]-2,6-dimethylmorpholinehydrochloride

MS m/e (ESI) 468 (MH⁺).

1-[4-(4-Butylpiperazin-1-yl)-3-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperidine-4-carbonitrilehydrochloride

MS m/e (ESI) 465 (MH⁺).

(S)-1-[4-(3-Methoxypyrrolidin-1-yl)-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-propylpiperazinehydrochloride

MS m/e (ESI) 442 (MH⁺).

(S)-1-Butyl-4-[4-(3-methoxypyrrolidin-1-yl)-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 456 (MH⁺).

(S)-1-Cyclopropylmethyl-4-[4-(3-methoxypyrrolidin-1-yl)-2-(3,3,5,5-tetramethylcyclohexylphenyl]piperazinehydrochloride

MS m/e (ESI) 454 (MH⁺).

1-[2-(4,4-Diethylcyclohexyl)-4-(4-ethoxypiperidin-1-yl)phenyl]-4-propylpiperazinehydrochloride

MS m/e (ESI) 470 (MH⁺).

1-Cyclopropylmethyl-4-[2-(4,4-dimethylcyclohexyl)-4-(4-ethoxypiperidin-1-yl)phenyl]piperazinehydrochloride

MS m/e (ESI) 482 (MH⁺).

1-Cyclopropylmethyl-4-[2-(4,4-dimethylcyclohexyl)-4-piperidin-1-ylphenyl]piperazinehydrochloride

MS m/e (ESI) 438 (MH⁺).

(R)-1-[2-(4,4-Diethylcyclohexyl)-4-(3-methoxypyrrolidin-1-yl)phenyl]-4-propylpiperazinehydrochloride

MS m/e (ESI) 442 (MH⁺).

(R)-1-Butyl-4-[2-(4,4-dimethylcyclohexyl)-4-(3-methoxypyrrolidin-1-yl)phenyl]piperazinehydrochloride

MS m/e (ESI) 428 (MH⁺).

(R)-1-[4-(3-Ethoxypyrrolidin-1-yl)-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-propylpiperazinehydrochloride

MS m/e (ESI) 456 (MH⁺).

(R)-1-Cyclopropylmethyl-4-[4-(3-ethoxypyrrolidin-1-yl)-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 468 (MH⁺).

1-[4-Fluoro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]-4-propylpiperazinehydrochloride

MS m/e (ESI) 359 (MH⁺).

1-[4-Fluoro-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-propylpiperazinehydrochloride

MS m/e (ESI) 361 (MH⁺).

1-Cyclopropylmethyl-4-[4-fluoro-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 373 (MH⁺).

1-Propyl-4-[4-pyridin-2-yl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinedihydrochloride

MS m/e (ESI) 420 (MH⁺).

1-Cyclopropylmethyl-4-[5-fluoro-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 373 (MH⁺).

4-(4-Cyclopropylmethylpiperazin-1-yl)-3-(3,3,5,5-tetramethylcyclohexyl)benzonitrilehydrochloride

MS m/e (ESI) 380 (MH⁺).

1-Cyclopropylmethyl-4-[3-fluoro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 371 (MH⁺).

2-Butyl-5-[2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]-2,5-diazabicyclo[2.2.1]heptanehydrochloride

MS m/e (ESI) 367 (MH⁺).

1-[2-(4-t-Butylcyclohex-1-enyl)phenyl]-4-(1-methylbutyl)piperazinehydrochloride

MS m/e (ESI) 369 (MH⁺).

1-[2-(4-t-Butylcyclohexyl)phenyl]-4-(1-methylbutyl)piperazinehydrochloride

MS m/e (ESI) 371 (MH⁺).

2-{4-[2-(4-t-Butylcyclohexyl)phenyl]piperazin-1-yl}-N-cyclohexylacetamidehydrochloride

MS m/e (ESI) 440 (MH⁺).

4-[2-(4-t-Butylcyclohexyl)phenyl]piperazine-1-carboxylic acid ethylamide

MS m/e (ESI) 372 (MH⁺).

3-{4-[2-(4-t-Butylcyclohexyl)phenyl]piperazin-1-yl}-1-methylpyrrolidin-2-onehydrochloride

MS m/e (ESI) 398 (MH⁺).

1-[2-(4-t-Butylcyclohexyl)phenyl]-4-isobutylpiperazinee hydrochloride

MS m/e (ESI) 357 (MH⁺).

1-[2-(4-t-Butylcyclohex-1-enyl)phenyl]-4-isobutylpiperazineehydrochloride

MS m/e (ESI) 355 (MH⁺).

2-{4-[2-(4-t-Butylcyclohexyl)phenyl]piperazin-1-yl}-1-(3,3-dimethylpiperidin-1-yl)ethanonehydrochloride

MS m/e (ESI) 454 (MH⁺).

1-Butyl-4-[2-(4-t-butylcyclohexyl)-4-thiophen-2-ylphenyl]piperazinehydrochloride

MS m/e (ESI) 439 (MH⁺).

1-Butyl-4-[2-(4-t-butylcyclohexyl)-4-methylphenyl]piperazinehydrochloride

MS m/e (ESI) 371 (MH⁺).

1-Butyl-4-[2-(4-t-butylcyclohexyl)-4-thiazol-2-ylphenyl]piperazinedihydrochloride

MS m/e (ESI) 440 (MH⁺).

1-Butyl-4-[2-(4-t-butylcyclohex-1-enyl)-4-fluorophenyl]piperazinehydrochloride

MS m/e (ESI) 373 (MH⁺).

1-Butyl-4-[2-(4-t-butylcyclohexyl)-4-fluorophenyl]piperazinehydrochloride

MS m/e (ESI) 375 (MH⁺).

1-Pentyl-4-[2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 369 (MH⁺).

1-Isobutyl-4-[2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 355 (MH⁺).

1-Pentyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 371 (MH⁺).

1-Isobutyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 357 (MH⁺).

1-Furan-3-ylmethyl-4-[2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 379 (MH⁺).

1-Isobutyl-4-[4-(4-methoxypiperidin-1-yl)-2-(3,35,5-tetramethylcyclohex-1-enyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 468 (MH⁺).

1-[4-(4-Methoxypiperidin-1-yl)-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-pentylpiperazinehydrochloride

MS m/e (ESI) 484 (MH⁺).

1-Isobutyl-4-[4-(4-methoxypiperidin-1-yl)-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 470 (MH⁺).

1-Furan-3-ylmethyl-4-[4-(4-methoxypiperidin-1-yl)-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 494 (MH⁺).

4-[4-(4-Isobutylpiperazine-1-yl)-3-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]morpholinehydrochloride

MS m/e (ESI) 440 (MH⁺).

4-[4-(4-Propylpiperazin-1-yl)-3-(3,3,5,5-tetramethylcyclohexyl)phenyl]morpholinehydrochloride

MS m/e (ESI) 428 (MH⁺).

4-[4-(4-Isobutylpiperazine-1-yl)-3-(3,3,5,5-tetramethylcyclohexyl)phenyl]morpholinehydrochloride

MS m/e (ESI) 442 (MH⁺).

1-Butyl-4-[4-(4-ethoxypiperidin-1-yl)-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 484 (MH⁺).

1-{4-[4-Piperidin-1-yl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazin-1-yl}butan-2-onehydrochloride

MS m/e (ESI) 454 (MH⁺).

1-[4-Piperidin-1-yl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-propylpiperazinehydrochloride

MS m/e (ESI) 426 (MH⁺).

1-Butyl-4-[4-piperidin-1-yl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 440 (MH⁺).

1-[4-(4-Cyclopropylmethylpiperazin-1-yl)-3-(3,3,5,5-tetramethylcyclohexyl)phenyl]azepanehydrochloride

MS m/e (ESI) 452 (MH⁺).

cis-4-[4-(4-Butylpiperazin-1-yl)-3-(3,3,5,5-tetramethylcyclohexyl)phenyl]-2,6-dimethylmorpholinehydrochloride

MS m/e (ESI) 470 (MH⁺).

1-[4-(4-Propylpiperazin-1-yl)-3-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperidine-4-carbonitrilehydrochloride

MS m/e (ESI) 451 (MH⁺).

1-Butyl-4-[2-(4,4-dimethylcyclohexyl)-4-(4-ethoxypiperidin-1-yl)phenyl]piperazinehydrochloride

MS m/e (ESI) 484 (MH⁺).

1-[2-(4,4-Diethylcyclohexyl)-4-piperidin-1-ylphenyl]-4-propylpiperazinehydrochloride

MS m/e (ESI) 426 (MH⁺).

(R)-1-Butyl-4-[4-(3-ethoxypyrrolidin-1-yl)-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 470 (MH⁺).

1-Butyl-4-[4-fluoro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 373 (MH⁺).

1-Cyclopropylmethyl-4-[4-fluoro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 371 (MH⁺).

1-[4-Fluoro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]-4-(tetrahydropyran-4-ylmethyl)piperazinehydrochloride

MS m/e (ESI) 415 (MH⁺).

1-Butyl-4-[4-fluoro-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 375 (MH⁺).

1-[4-Fluoro-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-(tetrahydropyran-4-ylmethyl)piperazinehydrochloride

MS m/e (ESI) 417 (MH⁺).

1-[5-Fluoro-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-propylpiperazinehydrochloride

MS m/e (ESI) 361 (MH⁺).

1-Butyl-4-[5-fluoro-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 375 (MH⁺).

1-[5-Fluoro-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-(tetrahydropyran-4-ylmethyl)piperazinehydrochloride

MS m/e (ESI) 417 (MH⁺).

4-(4-Butylpiperazin-1-yl)-3-(3,3,5,5-tetramethylcyclohexyl)benzonitrilehydrochloride

MS m/e (ESI) 382 (MH⁺).

4-[4-(Tetrahydropyran-4-ylmethyl)piperazin-1-yl]-3-(3,3,5,5-tetramethylcyclohexyl)benzonitrilehydrochloride

MS m/e (ESI) 424 (MH⁺).

1-(Tetrahydropyran-4-ylmethyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)-4-thiazol-2-ylphenyl]piperazinedihydrochloride

MS m/e (ESI) 482 (MH⁺).

1-Butyl-4-[3-fluoro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 373 (MH⁺).

2-{4-[2-(3,3,5,5-Tetramethylcyclohexyl)phenyl]piperazin-1-ylmethyl}cyclopropanecarboxylicacid methylamide hydrochloride

MS m/e (ESI) 412 (MH⁺).

cis-2-{4-[2-(3,3,5,5-Tetramethylcyclohexyl)phenyl]piperazin-1-ylmethyl}cyclopropanecarboxylicacid dimethylamide hydrochloride

MS m/e (ESI) 426 (MH⁺).

1-(1-Methylcyclopropylmethyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 369 (MH⁺).

1-[2-(4-t-Butylcyclohexyl)phenyl]-4-propylpiperazine hydrochloride

MS m/e (ESI) 343 (MH⁺).

1-Butyl-4-[2-(3,5-dimethylcyclohexyl)phenyl]piperazine hydrochloride

MS m/e (ESI) 329 (MH⁺).

1-Butyl-4-[2-(4-trifluoromethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 369 (MH⁺).

1-{4-[2-(4-t-Butylcyclohexyl)phenyl]piperazin-1-yl}butan-1-one

MS m/e (ESI) 393 (MNa⁺).

1-Butyl-4-[2-(4-phenylcyclohexyl)phenyl]piperazine hydrochloride

MS m/e (ESI) 377 (MH⁺).

3-[4-(4-t-Butylcyclohexyl)-3-(4-butylpiperazine-1-yl)phenyl]propionicacid methyl ester hydrochloride

MS m/e (ESI) 443 (MH⁺).

[4-(4-t-Butylcyclohexyl)-3-(4-butylpiperazine-1-yl)phenoxy]acetic acidethyl ester hydrochloride

MS m/e (ESI) 459 (MH⁺).

1-[2-(4-t-Butylcyclohexyl)-4-piperidin-1-ylphenyl]-4-cyclopropylmethylpiperazinehydrochloride

MS m/e (ESI) 438 (MH⁺).

1-[2-(4-t-Butylcyclohexyl)-4-piperidin-1-ylphenyl]-4-propylpiperazinehydrochloride

MS m/e (ESI) 426 (MH⁺).

4-[4-(4-t-Butylcyclohexyl)-5-(4-butylpiperazine-1-yl)-2-methoxyphenyl]morpholinehydrochloride

MS m/e (ESI) 472 (MH⁺).

1-Butyl-4-[2-(4-t-butylcyclohexyl)-5-methoxy-4-(4-methoxypiperidin-1-yl)phenyl]piperazinehydrochloride

MS m/e (ESI) 500 (MH⁺).

1-Butyl-4-[2-(4-t-butylcyclohexyl)-4-(4-ethoxypiperidin-1-yl)-5-methoxyphenyl]piperazinehydrochloride

MS m/e (ESI) 514 (MH⁺).

1-[2-(4-t-Butylcyclohexyl)-5-methoxy-4-(4-methoxypiperidin-1-yl)phenyl]-4-cyclopropylmethylpiperazinehydrochloride

MS m/e (ESI) 498 (MH⁺).

1-Butyl-4-[2-(4,4-diethylcyclohex-1-enyl)-5-methoxyphenyl]piperazinehydrochloride

MS m/e (ESI) 385 (MH⁺).

1-Butyl-4-[2-(4,4-dimethylcyclohexyl)-5-methoxyphenyl]piperazinehydrochloride

MS m/e (ESI) 387 (MH⁺).

1-[2-(4,4-Diethylcyclohexyl)-5-methoxyphenyl]-4-propylpiperazinehydrochloride

MS m/e (ESI) 373 (MH⁺).

1-Butyl-4-[5-methoxy-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 385 (MH⁺).

1-[5-Methoxy-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]-4-propylpiperazinehydrochloride

MS m/e (ESI) 371 (MH⁺).

1-[5-Methoxy-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-propylpiperazinehydrochloride

MS m/e (ESI) 373 (MH⁺).

4-[5-(4,4-Diethylcyclohexyl)-2-methoxy-4-(4-propylpiperazin-1-yl)phenyl]morpholinehydrochloride

MS m/e (ESI) 458 (MH⁺).

1-Butyl-4-[2-(4,4-dimethylcyclohex-1-enyl)-5-methoxyphenyl]piperazinehydrochloride

MS m/e (ESI) 357 (MH⁺).

1-Butyl-4-[2-(4,4-dimethylcyclohexyl)-5-methoxyphenyl]piperazinehydrochloride

MS m/e (ESI) 359 (MH⁺).

1-[2-(4,4-Dimethylcyclohex-1-enyl)-5-methoxyphenyl]-4-propylpiperazinehydrochloride

MS m/e (ESI) 343 (MH⁺).

1-[2-(4,4-Dimethylcyclohexyl)-5-methoxyphenyl]-4-propylpiperazinehydrochloride

MS m/e (ESI) 345 (MH⁺).

1-Cyclopropylmethyl-4-[2-(4,4-dimethylcyclohex-1-enyl)-5-methoxyphenyl]piperazinehydrochloride

MS m/e (ESI) 355 (MH⁺).

1-Cyclopropylmethyl-4-[2-(4,4-dimethylcyclohexyl)-5-methoxyphenyl]piperazinehydrochloride

MS m/e (ESI) 357 (MH⁺).

1-[2-(4,4-Dimethylcyclohex-1-enyl)-5-methoxyphenyl]-4-(tetrahydropyran-4-ylmethyl)piperazinehydrochloride

MS m/e (ESI) 399 (MH⁺).

1-[2-(4,4-Dimethylcyclohexyl)-5-methoxyphenyl]-4-(tetrahydropyran-4-ylmethyl)piperazinehydrochloride

MS m/e (ESI) 401 (MH⁺).

1-[2-(4,4-Dimethylcyclohex-1-enyl)-5-methoxyphenyl]-4-pentylpiperazinehydrochloride

MS m/e (ESI) 371 (MH⁺).

1-Cyclopropylmethyl-4-[5-methoxy-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 383 (MH⁺).

1-Cyclopropylmethyl-4-[5-methoxy-2-(3,355-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 385 (MH⁺).

1-Butyl-4-(2-spiro[4.5]dec-7-en-8-ylphenyl)piperazine hydrochloride

MS m/e (ESI) 353 (MH⁺).

1-Cyclopropylmethyl-4-(2-spiro[4.5]dec-7-en-8-ylphenyl)piperazinehydrochloride

MS m/e (ESI) 351 (MH⁺).

1-Cyclopropylmethyl-4-(2-spiro[4.5]dec-8-ylphenyl)piperazinehydrochloride

MS m/e (ESI) 353 (MH⁺).

1-(2-Spiro[4.5]dec-7-en-8-ylphenyl)-4-(tetrahydropyran-4-ylmethyl)piperazinehydrochloride

MS m/e (ESI) 395 (MH⁺).

1-[4-(2-Spiro[4.5]dec-7-en-8-ylphenyl)piperazin-1-yl]butan-2-onehydrochloride

MS m/e (ESI) 367 (MH⁺).

1-[4-(2-Spiro[4.5]dec-8-ylphenyl)piperazin-1-yl]butan-2-onehydrochloride

MS m/e (ESI) 369 (MH⁺).

1-{4-[2-(4,4-Dimethylcyclohex-1-enyl)-5-methoxyphenyl]piperazin-1-yl}butan-2-onehydrochloride

MS m/e (ESI) 371 (MH⁺).

[2-Methoxy-4-(4-propylpiperazin-1-yl)-5-(3,3,5,5-tetramethylcyclohexyl)phenyl]dimethylaminehydrochloride

MS m/e (ESI) 416 (MH⁺).

4-[4-(4-Propylpiperazin-1-yl)-3-spiro[4.5]dec-7-en-8-ylphenyl]morpholinehydrochloride

MS m/e (ESI) 424 (MH⁺).

4-[4-(4-Butylpiperazin-1-yl)-3-spiro[4.5]dec-7-en-8-ylphenyl]morpholinehydrochloride

MS m/e (ESI) 438 (MH⁺).

4-[4-(4-Cyclopropylmethylpiperazin-1-yl)-3-spiro[4.5]dec-7-en-8-ylphenyl]morpholinehydrochloride

MS m/e (ESI) 436 (MH⁺).

4-{3-Spiro[4.5]dec-7-en-8-Yl-4-[4-(tetrahydropyran-4-Ylmethyl)piperazin-1-yl]phenyl}morpholinehydrochloride

MS m/e (ESI) 480 (MH⁺).

4-[4-(4-Butylpiperazin-1-yl)-3-spiro[4.5]dec-8-ylphenyl]morpholinehydrochloride

MS m/e (ESI) 440 (MH⁺).

4-[4-(4-Cyclopropylmethylpiperazin-1-yl)-3-spiro[4.5]dec-8-ylphenyl]morpholinehydrochloride

MS m/e (ESI) 438 (MH⁺).

4-{3-Spiro[4.5]dec-8-yl-4-[4-(tetrahydropyran-4-ylmethyl)piperazin-1-yl]phenyl}morpholinehydrochloride

MS m/e (ESI) 482 (MH⁺).

1-[4-(4-Morpholin-4-yl-2-spiro[4.5]dec-8-ylphenyl)piperazin-1-yl]butan-2-onehydrochloride

MS m/e (ESI) 454 (MH⁺).

1-[4-(4-Methoxypiperidin-1-yl)-2-spiro[4.5]dec-7-en-8-ylphenyl]-4-propylpiperazinehydrochloride

MS m/e (ESI) 452 (MH⁺).

1-Butyl-4-[4-(4-methoxypiperidin-1-yl)-2-spiro[4.5]dec-7-en-8-ylphenyl]piperazinehydrochloride

MS m/me (ESI) 466 (MH⁺).

1-[4-(4-Methoxypiperidin-1-yl)-2-spiro[4.5]dec-7-en-8-ylphenyl]-4-pentylpiperazinehydrochloride

MS m/e (ESI) 480 (MH⁺).

1-[4-(4-Methoxypiperidin-1-yl)-2-spiro[4.5]dec-7-en-8-ylphenyl]-4-(tetrahydropyran-4-ylmethyl)piperazinehydrochloride

MS m/e (ESI) 508 (MH⁺).

1-Butyl-4-[4-(4-methoxypiperidin-1-yl)-2-spiro[4.5]dec-8-ylphenyl]piperazinehydrochloride

MS m/e (ESI) 468 (MH⁺).

1-[4-(4-Methoxypiperidin-1-yl)-2-spiro[4.5]dec-8-ylphenyl]-4-(tetrahydropyran-4-ylmethyl)piperazinehydrochloride

MS m/e (ESI) 510 (MH⁺).

1-{4-[4-(4-Methoxypiperidin-1-yl)-2-spiro[4.5]dec-8-ylphenyl]piperazin-1-yl}butan-2-onehydrochloride

MS m/e (ESI) 482 (MH⁺).

[2-Methoxy-4-(4-pentylpiperazin-1-yl)-5-(3,3,5,5-tetramethylcyclohexyl)phenyl]dimethylaminehydrochloride

MS m/e (ESI) 444 (MH⁺).

[4-(4-Cyclopropylmethylpiperazin-1-yl)-2-methoxy-5-(3,3,5,5-tetramethylcyclohexyl)phenyl]dimethylaminehydrochloride

MS m/e (ESI) 428 (MH⁺).

[2-Methoxy-4-[4-(tetrahydropyran-4-ylmethyl)piperazin-1-yl]-5-(3,3,5,5-tetramethylcyclohexyl)phenyl]dimethylaminehydrochloride

MS m/e (ESI) 472 (MH⁺).

1-Cyclopropylmethyl-4-(4-piperidin-1-yl-2-spiro[4.5]dec-8-ylphenyl)piperazinehydrochloride

MS m/e (ESI) 436 (MH⁺).

1-Propyl-4-(4-pyrrolidin-1-yl-2-spiro[4.5]dec-8-ylphenyl)piperazinehydrochloride

MS m/e (ESI) 410 (MH⁺).

1-Cyclopropylmethyl-4-(4-pyrrolidin-1-yl-2-spiro[4.5]dec-8-ylphenyl)piperazinehydrochloride

MS m/e (ESI) 422 (MH⁺).

1-[5-Methoxy-4-pyrrolidin-1-yl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-propylpiperazinehydrochloride

MS m/e (ESI) 442 (MH⁺).

cis-2,6-Dimethyl-4-[4-(4-propylpiperazin-1-yl)-3-spiro[4.5]dec-8-ylphenyl]morpholinehydrochloride

MS m/e (ESI) 454 (MH⁺).

cis-4-[4-(4-Butylpiperazin-1-yl)-3-spiro[4.5]dec-8-ylphenyl]-2,6-dimethylmorpholinehydrochloride

MS m/e (ESI) 468 (MH⁺).

cis-4-[4-(4-Cyclopropylmethylpiperazin-1-yl)-3-spiro[4.5]dec-8-ylphenyl]-2,6-dimethylmorpholinehydrochloride

MS m/e (ESI) 466 (MH⁺).

4-[2-Ethoxy-4-(4-pentylpiperazin-1-yl)-5-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]morpholinehydrochloride

MS m/e (ESI) 498 (MH⁺).

4-[2-Ethoxy-4-[4-(tetrahydropyran-4-ylmethyl)piperazin-1-yl]-5-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]morpholinehydrochloride

MS m/e (ESI) 526 (MH⁺).

4-[2-Ethoxy-4-(4-propylpiperazin-1-yl)-5-(3,3,5,5-tetramethylcyclohexyl)phenyl]morpholinehydrochloride

MS m/e (ESI) 472 (MH⁺).

1-Cyclopropylmethyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-1,2,3,6-tetrahydropyridinehydrochloride

MS m/e (ESI) 352 (MH⁺).

1-Propyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperidinehydrochloride

MS m/e (ESI) 342 (MH⁺).

1-Propyl-4-[2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperidinehydrochloride

MS m/e (ESI) 340 (MH⁺).

1-Butyl-4-[2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperidinehydrochloride

MS m/e (ESI) 354 (MH⁺).

1-Cyclopropylmethyl-4-[2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperidinehydrochloride

MS m/e (ESI) 352 (MH⁺).

1-(2-Fluoroethyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperidinehydrochloride

MS m/e (ESI) 346 (MH⁺).

1-(3-Fluoropropyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperidinehydrochloride

MS m/e (ESI) 360 (MH⁺).

1-(4-Fluorobutyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperidinehydrochloride

MS m/e (ESI) 374 (MH⁺).

1-Cyclopropylmethyl-4-[4-methyl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-1,2,3,6-tetrahydropyridinehydrochloride

MS m/e (ESI) 366 (MH⁺).

1-Butyl-4-[4-methyl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperidinehydrochloride

MS m/e (ESI) 370 (MH⁺).

1-Cyclopropylmethyl-4-[4-methyl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperidinehydrochloride

MS m/e (ESI) 368 (MH⁺).

4-[4-Fluoro-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-1-propyl-1,2,3,6-tetrahydropyridinehydrochloride

MS m/e (ESI) 358 (MH⁺).

1-Butyl-4-[4-fluoro-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-1,2,3,6-tetrahydropyridinehydrochloride

MS m/e (ESI) 372 (MH⁺).

1-Cyclopropylmethyl-4-[4-fluoro-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-1,2,3,6-tetrahydropyridinehydrochloride

MS m/e (ESI) 370 (MH⁺).

4-[4-Fluoro-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-1-propylpiperidinehydrochloride

MS m/e (ESI) 360 (MH⁺).

1-Butyl-4-[4-fluoro-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperidinehydrochloride

MS m/e (ESI) 374 (MH⁺).

1-Cyclopropylmethyl-4-[4-fluoro-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperidinehydrochloride

MS m/e (ESI) 372 (MH⁺).

1-Propyl-3-[2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]pyrrolidinehydrochloride

MS m/e (ESI) 326 (MH⁺).

1-Butyl-3-[2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]pyrrolidinehydrochloride

MS m/e (ESI) 340 (MH⁺).

1-Cyclopropylmethyl-3-[2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]pyrrolidinehydrochloride

MS m/e (ESI) 338 (MH⁺).

1-Propyl-3-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]pyrrolidinehydrochloride

MS m/e (ESI) 328 (MH⁺).

1-Butyl-3-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]pyrrolidinehydrochloride

MS m/e (ESI) 342 (MH⁺).

1-Cyclopropylmethyl-3-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]pyrrolidinehydrochloride

MS m/e (ESI) 340 (MH⁺).

1-Cyclopropylmethyl-4-[5-fluoro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperidinehydrochloride

MS m/e (ESI) 370 (MH⁺).

4-[5-Fluoro-2-(3,3,5,5-tetramethylcyclohexylphenyl]-1-propylpiperidinehydrochloride

MS m/e (ESI) 360 (MH⁺).

1-Cyclopropylmethyl-4-[5-fluoro-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperidinehydrochloride

MS m/e (ESI) 372 (MH⁺).

1-Propyl-4-[2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]azepanehydrochloride

MS m/e (ESI) 354 (MH⁺).

1-Butyl-4-[2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]azepanehydrochloride

MS m/e (ESI) 368 (MH⁺).

1-Cyclopropylmethyl-4-[2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]azepanehydrochloride

MS m/e (ESI) 366 (MH⁺).

1-Propyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]azepanehydrochloride

MS m/e (ESI) 356 (MH⁺).

1-Butyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]azepane hydrochloride

MS m/e (ESI) 370 (MH⁺).

1-Cyclopropylmethyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]azepanehydrochloride

MS m/e (ESI) 368 (MH⁺).

4-[3-Fluoro-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-1-propyl-1,2,3,6-tetrahydropyridinehydrochloride

MS m/e (ESI) 358 (MH⁺).

1-Cyclopropylmethyl-4-[3-fluoro-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]1,2,3,6-tetrahydropyridinehydrochloride

MS m/e (ESI) 370 (MH⁺).

4-[3-Fluoro-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-1-propylpiperidinehydrochloride

MS m/e (ESI) 360 (MH⁺).

1-Butyl-4-[3-fluoro-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperidinehydrochloride

MS m/e (ESI) 374 (MH⁺).

1-Cyclopropylmethyl-4-[3-fluoro-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperidinehydrochloride

MS m/e (ESI) 372 (MH⁺).

1-Butyl-4-[2-fluoro-6-(3,3,5,5-tetramethylcyclohexyl)phenyl)piperidinehydrochloride

MS m/e (ESI) 374 (MH⁺).

1-Butyl-4-[2-(4-t-butylcyclohex-1-enyl)phenyl]piperazine hydrochloride

MS m/e (ESI) 355 (MH⁺).

1-Butyl-4-[2-(4-t-butylcyclohex-1-enyl)-5-fluorophenyl]piperazinehydrochloride

MS m/e (ESI) 373 (MH⁺).

1-Butyl-4-[2-(4-t-butylcyclohexyl)-5-trifluoromethylphenyl]piperazinehydrochloride

MS m/e (ESI) 425 (MH⁺).

1-Butyl-4-[5-t-butyl-2-(4-t-butylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 413 (MH⁺).

[4-(4-t-Butylcyclohexyl)-3-(4-butylpiperazine-1-yl)phenyl]acetic acid

MS m/e (ESI) 413 (M⁻).

1-{4-[2-(4-t-Butylcyclohex-1-enyl)phenyl]piperazin-1-yl}butan-1-one

MS m/e (ESI) 391 (MNa⁺).

2-{4-[2-(4-t-Butylcyclohex-1-enyl)phenyl]piperazin-1-yl}-N,N-dimethylacetamidehydrochloride

MS m/e (ESI) 384 (MH⁺).

1-[2-(4-t-Butylcyclohexyl)phenyl]-4-(propane-1-sulfonyl)piperazine

MS m/e (ESI) 429 (MNa⁺).

2-{4-[2-(4-t-Butylcyclohexyl)phenyl]piperazin-1-yl}-1-phenylethanonehydrochloride

MS m/e (ESI) 419 (MH⁺).

1-Butyl-4-[2-(4-t-butylcyclohex-1-enyl)-4-piperidin-1-ylphenyl]piperazinehydrochloride

MS m/e (ESI) 438 (MH⁺).

1-Butyl-4-[2-(4-t-butylcyclohexyl)-4-piperidin-1-ylphenyl]piperazinehydrochloride

MS m/e (ESI) 440 (MH⁺).

1-Butyl-4-[2-(4-t-butylcyclohexyl)-5-methoxy-4-piperidin-1-ylphenyl]piperazinehydrochloride

MS m/e (ESI) 470 (MH⁺).

4-[5-(4-t-Butylcyclohexyl)-4-(4-butylpiperazine-1-yl)-2-methoxyphenyl]-2,6-cis-dimethylmorpholinehydrochloride

MS m/e (ESI) 500 (MH⁺).

1-[2-(4-t-Butylcyclohexyl)-4-(piperidin-1-yl)phenyl]-4-(tetrahydropyran-4-ylmethyl)piperazinehydrochloride

MS m/e (ESI) 482 (MH⁺).

1-{4-[2-(4-t-Butylcyclohexyl)-5-methoxy-4-(4-methoxypiperidin-1-yl)phenyl]piperazin-1-yl}butan-1-one

MS m/e (ESI) 514 (MH⁺).

1-[2-(4-t-Butylcyclohexyl)-5-methoxy-4-(4-methoxypiperidin-1-yl)phenyl]-4-(tetrahydropyran-4-ylmethyl)piperazinehydrochloride

MS m/e (ESI) 542 (MH⁺).

1-[2-(4-t-Butylcyclohexyl)-5-methoxy-4-(4-methoxypiperidin-1-yl)phenyl]-4-propylpiperazinehydrochloride

MS m/e (ESI) 486 (MH⁺).

1-[2-(4,4-Diethylcyclohex-1-enyl)-5-methoxyphenyl]-4-(tetrahydropyran-4-ylmethyl)piperazinehydrochloride

MS m/e (ESI) 427 (MH⁺).

[5-(4,4-Diethylcyclohexyl)-2-methoxy-4-(4-propylpiperazin-1-yl)phenyl]dimethylaminehydrochloride

MS m/e (ESI) 416 (MH⁺).

1-[5-Methoxy-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]-4-pentylpiperazinehydrochloride

MS m/e (ESI) 399 (MH⁺).

1-[5-Methoxy-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-pentylpiperazinehydrochloride

MS m/e (ESI) 401 (MH⁺).

1-Pentyl-4-(2-spiro[4.5]dec-7-en-8-ylphenyl)piperazine hydrochloride

MS m/e (ESI) 367 (MH⁺).

1-Pentyl-4-(2-spiro[4.5]dec-8-ylphenyl)piperazine hydrochloride

MS m/e (ESI) 369 (MH⁺).

1-{4-[2-(4,4-Dimethylcyclohexyl)-5-methoxyphenyl]piperazin-1-yl}butan-2-onehydrochloride

MS m/e (ESI) 373 (MH⁺).

1-[4-(4-Morpholin-4-yl-2-spiro[4.5]dec-7-en-8-ylphenyl)piperazin-1-yl]butan-2-onehydrochloride

MS m/e (ESI) 452 (MH⁺).

4-[4-(4-Propylpiperazin-1-yl)-3-spiro[4.5]dec-8-ylphenyl]morpholinehydrochloride

MS m/e (ESI) 426 (MH⁺).

4-[4-(4-Pentylpiperazin-1-yl)-3-spiro[4.5]dec-8-ylphenyl]morpholinehydrochloride

MS m/e (ESI) 454 (MH⁺).

1-Cyclopropylmethyl-4-[4-(4-methoxypiperidin-1-yl)-2-spiro[4.5]dec-7-en-8-ylphenyl]piperazinehydrochloride

MS m/e (ESI) 464 (MH⁺).

1-{4-[4-(4-Methoxypiperidin-1-yl)-2-spiro[4.5]dec-7-en-8-ylphenyl]piperazin-1-yl}butan-2-onehydrochloride

MS m/e (ESI) 480 (MH⁺).

1-[4-(4-Methoxypiperidin-1-yl)-2-spiro[4.5]dec-8-ylphenyl]-4-pentylpiperazinehydrochloride

MS m/e (ESI) 482 (MH⁺).

1-Cyclopropylmethyl-4-[4-(4-methoxypiperidin-1-yl)-2-spiro[4.5]dec-8-ylphenyl]piperazinehydrochloride

MS m/e (ESI) 466 (MH⁺).

1-Butyl-4-(4-piperidin-1-yl-2-spiro[4.5]dec-8-ylphenyl)piperazinehydrochloride

MS m/e (ESI) 438 (MH⁺).

1-(4-Piperidin-1-yl-2-spiro[4.5]dec-8-ylphenyl)-4-(tetrahydropyran-4-ylmethyl)piperazinehydrochloride

MS m/e (ESI) 480 (MH⁺).

1-(4-Pyrrolidin-1-yl-2-spiro[4.5]dec-8-ylphenyl)-4-(tetrahydropyran-4-ylmethyl)piperazinehydrochloride

MS m/e (ESI) 466 (MH⁺).

1-Butyl-4-[5-methoxy-4-pyrrolidin-1-yl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 456 (MH⁺).

cis-2,6-Dimethyl-4-{3-spiro[4.5]dec-8-yl-4-[4-(tetrahydropyran-4-ylmethyl)piperazin-1-yl]phenyl}morpholinehydrochloride

MS m/e (ESI) 510 (MH⁺).

4-[2-Ethoxy-4-(4-pentylpiperazin-1-yl)-5-(3,3,5,5-tetramethylcyclohexyl)phenyl]morpholinehydrochloride

MS m/e (ESI) 500 (MH⁺).

4-[4-(4-Cyclopropylmethylpiperazin-1-yl)-2-ethoxy-5-(3,3,5,5-tetramethylcyclohexyl)phenyl]morpholinehydrochloride

MS m/e (ESI) 484 (MH⁺).

1-Propyl-4-[2-(3,3,5,5-tetramethylcyclohex-1-enyl)-5-trifluoromethylphenyl]piperazinehydrochloride

MS m/e (ESI) 409 (MH⁺).

1-Cyclopropylmethyl-4-[2-(3,3,5,5-tetramethylcyclohex-1-enyl)-5-trifluoromethylphenyl]piperazinehydrochloride

MS m/e (ESI) 421 (MH⁺).

1-Cyclopropylmethyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)-5-trifluoromethylphenyl]piperazinehydrochloride

MS m/e (ESI) 423 (MH⁺).

1-Propyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-1,2,3,6-tetrahydropyridinehydrochloride

MS m/e (ESI) 340 (MH⁺).

1-Cyclopropylmethyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperidinehydrochloride

MS m/e (ESI) 354 (MH⁺).

1-Butyl-4-[4-methyl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-1,2,3,6-tetrahydropyridinehydrochloride

MS m/e (ESI) 368 (MH⁺).

4-[5-Fluoro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]-1-propylpiperidinehydrochloride

MS m/e (ESI) 358 (MH⁺).

1-Butyl-4-[3-fluoro-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-1,2,3,6-tetrahydropyridinehydrochloride

MS m/e (ESI) 372 (MH⁺).

1-Butyl-4-[2-fluoro-6-(3,3,5,5-tetramethylcyclohexyl)phenyl]-1,2,3,6-tetrahydropyridinehydrochloride

MS m/e (ESI) 372 (MH⁺).

1-Butyl-4-[2-(4-t-butylcyclohexyl)-4,5-dimethoxyphenyl]piperazinehydrochloride

MS m/e (ESI) 417 (MH⁺).

1-Butyl-4-[2-(4-t-butylcyclohexyl)-6-methoxyphenyl]piperazinehydrochloride

MS m/e (ESI) 387 (MH⁺).

1-Butyl-4-[2-(4-t-butylcyclohex-1-enyl)-5-methoxyphenyl]piperazinehydrochloride

MS m/e (ESI) 385 (MH⁺).

1-Butyl-4-[2-(4-t-butylcyclohexyl)-5-ethoxyphenyl]piperazinehydrochloride

MS m/e (ESI) 401 (MH⁺).

1-[2-(4,4-Dimethylcyclohex-1-enyl)phenyl]-4-propylpiperazinehydrochloride

MS m/e (ESI) 313 (MH⁺).

1-Butyl-4-[2-(4,4-dimethylcyclohexyl)phenyl]piperazine hydrochloride

MS m/e (ESI) 329 (MH⁺).

1-[2-(4,4-Dimethylcyclohexyl)phenyl]-4-propylpiperazine hydrochloride

MS m/e (ESI) 315 (MH⁺).

1-{4-[2-(4,4-Dimethylcyclohexyl)phenyl]piperazin-1-yl}butan-1-one

MS m/e (ESI) 343 (MH⁺).

1-Butyl-4-(2-cyclohex-1-enylphenyl)piperazine hydrochloride

MS m/e (ESI) 299 (MH⁺).

{4-[2-(4-t-Butylcyclohexyl)phenyl]piperazin-1-yl}acetonitrilehydrochloride

MS m/e (ESI) 340 (MH⁺).

2-{4-[2-(4-t-Butylcyclohex-1-enyl)-4-morpholin-4-ylphenyl]piperazin-1-yl}-N-ethylacetamidehydrochloride

MS m/e (ESI) 469 (MH⁺).

4-[3-(4-t-Butylcyclohexyl)-4-(4-pentylpiperazin-1-yl)phenyl]morpholinehydrochloride

MS m/e (ESI) 456 (MH⁺).

4-[3-(4-t-Butylcyclohex-1-enyl)-4-(4-propylpiperazin-1-yl)phenyl]morpholinehydrochloride

MS m/e (ESI) 426 (MH⁺).

4-[3-(4-t-Butylcyclohexyl)-4-(4-propylpiperazin-1-yl)phenyl]morpholinehydrochloride

MS m/e (ESI) 428 (MH⁺).

4-{3-(4-t-Butylcyclohexyl)-4-[4-(3-methylbutyl)piperazin-1-yl]phenyl}morpholinehydrochloride

MS m/e (ESI) 456 (MH⁺).

4-{3-(4-t-Butylcyclohexyl)-4-[4-(tetrahydropyran-4-ylmethyl)piperazin-1-yl]phenyl}morpholinehydrochloride

MS m/e (ESI) 484 (MH⁺).

1-[2-(4-t-Butylcyclohexyl)phenyl]-4-(2-ethoxyethyl)piperazinehydrochloride

MS m/e (ESI) 373 (MH⁺).

1-[2-(4-t-Butylcyclohex-1-enyl)phenyl]-4-(2-ethoxyethyl)piperazinehydrochloride

MS m/e (ESI) 371 (MH⁺).

4-{3-(4-t-Butylcyclohex-1-enyl)-4-[4-(3-methylbutyl)piperazin-1-yl]phenyl}morpholinehydrochloride

MS m/e (ESI) 454 (MH⁺).

4-{3-(4-t-Butylcyclohex-1-enyl)-4-[4-(tetrahydropyran-4-ylmethyl)piperazin-1-yl]phenyl}morpholinehydrochloride

MS m/e (ESI) 482 (MH⁺).

1-[2-(4-t-Butylcyclohexyl)phenyl]-4-(tetrahydrofuran-3-ylmethyl)piperazinehydrochloride

MS m/e (ESI) 385 (MH⁺).

1-Butyl-4-[2-(4,4-dimethylcyclohexyl)-4-(4-methoxypiperidin-1-yl)phenyl]piperazinehydrochloride

MS m/e (ESI) 442 (MH⁺).

1-[2-(4-t-Butylcyclohex-1-enyl)phenyl]-4-(tetrahydropyran-4-ylmethyl)piperazinehydrochloride

MS m/e (ESI) 397 (MH⁺).

1-Butyl-4-[2-(4,4-dimethylcyclohexyl)-4-piperidin-1-ylphenyl]piperazinehydrochloride

MS m/e (ESI) 412 (MH⁺).

[4-(4-Butylpiperazin-1-yl)-3-(4,4-dimethylcyclohexyl)phenyl]dimethylaminehydrochloride

MS m/e (ESI) 372 (MH⁺).

1-[2-(4,4-Dimethylcyclohexyl)phenyl]-4-(tetrahydropyran-4-ylmethyl)piperazinehydrochloride

MS m/e (ESI) 371 (MH⁺).

1-Propyl-4-(2-spiro[2.5]oct-5-en-6-ylphenyl)piperazine hydrochloride

MS m/e (ESI) 311 (MH⁺).

1-Cyclopropylmethyl-4-(2-spiro[2.5]oct-5-en-6-ylphenyl)piperazinehydrochloride

MS m/e (ESI) 323 (MH⁺).

1-Propyl-4-(2-spiro[2.5]oct-6-ylphenyl)piperazine hydrochloride

MS m/e (ESI) 313 (MH⁺).

1-Cyclopropylmethyl-4-(2-spiro[2.5]oct-6-ylphenyl)piperazinehydrochloride

MS m/e (ESI) 325 (MH⁺).

1-(2-Spiro[2.5]oct-6-ylphenyl)-4-(tetrahydropyran-4-ylmethyl)piperazinehydrochloride

MS m/e (ESI) 369 (MH⁺).

1-Butyl-4-(2-spiro[2.5]oct-6-ylphenyl)piperazine hydrochloride

MS m/e (ESI) 327 (MH⁺).

1-[4-(2-Spiro[2.5]oct-6-ylphenyl)piperazin-1-yl]butan-2-onehydrochloride

MS m/e (ESI) 341 (MH⁺).

1-Pentyl-4-(2-spiro[2.5]oct-5-en-6-ylphenyl)piperazine hydrochloride

MS m/e (ESI) 339 (MH⁺).

1-Pentyl-4-(2-spiro[2.5]oct-6-ylphenyl)piperazine hydrochloride

MS m/e (ESI) 341 (MH⁺).

1-Butyl-4-[4-(4-methoxypiperidin-1-yl)-2-spiro[2.5]oct-6-ylphenyl]piperazinehydrochloride

MS m/e (ESI) 440 (MH⁺).

1-Butyl-4-[4-(4-ethoxypiperidin-1-yl)-2-spiro[2.5]oct-6-ylphenyl]piperazinehydrochloride

MS m/e (ESI) 454 (MH⁺).

1-Butyl-4-(4-piperidin-1-yl-2-spiro[2.5]oct-6-ylphenyl)piperazinehydrochloride

MS m/e (ESI) 410 (MH⁺).

1-[2-(4,4-Dimethylcyclohexyl)-4-(4-ethoxypiperidin-1-yl)phenyl]-4-pentylpiperazinehydrochloride

MS m/e (ESI) 470 (MH⁺).

1-[2-(4,4-Dimethylcyclohexyl)-4-(4-ethoxypiperidin-1-yl)phenyl]-4-propylpiperazinehydrochloride

MS m/e (ESI) 442 (MH⁺).

1-Cyclopropylmethyl-4-[2-(4,4-dimethylcyclohexyl)-4-(4-ethoxypiperidin-1-yl)phenyl]piperazinehydrochloride

MS m/e (ESI) 454 (MH⁺).

1-[2-(4,4-Dimethylcyclohexyl)-4-(4-ethoxypiperidin-1-yl)phenyl]-4-(tetrahydropyran-4-ylmethyl)piperazinehydrochloride

MS m/e (ESI) 498 (MH⁺).

1-Butyl-4-(4-pyrrolidin-1-yl-2-spiro[2.5]oct-6-ylphenyl)piperazinehydrochloride

MS m/e (ESI) 396 (MH⁺).

1-(4-Piperidin-1-yl-2-spiro[2.5]oct-6-ylphenyl)-4-propylpiperazinehydrochloride

MS m/e (ESI) 396 (MH⁺).

1-Cyclopropylmethyl-4-(4-piperidin-1-yl-2-spiro[2.5]oct-6-ylphenyl)piperazinehydrochloride

MS m/e (ESI) 408 (MH⁺).

1-(4-Piperidin-1-yl-2-spiro[2.5]oct-6-ylphenyl)-4-(tetrahydropyran-4-ylmethyl)piperazinehydrochloride

MS m/e (ESI) 452 (MH⁺).

1-(2-Ethoxyethyl)-4-(4-piperidin-1-yl-2-spiro[2.5]oct-6-ylphenyl)piperazinehydrochloride

MS m/e (ESI) 426 (MH⁺).

1-(2-Methoxyethyl)-4-(4-piperidin-1-yl-2-spiro[2.5]oct-6-ylphenyl)piperazinehydrochloride

MS m/e (ESI) 412 (MH⁺).

1-Cyclobutylmethyl-4-[2-(4,4-dimethylcyclohexyl)-4-(4-ethoxypiperidin-1-yl)phenyl]piperazinehydrochloride

MS m/e (ESI) 468 (MH⁺).

cis-2,6-Dimethyl-4-[4-(4-pentylpiperazin-1-yl)-3-spiro[2.5]oct-6-ylphenyl]morpholinehydrochloride

MS m/e (ESI) 454 (MH⁺).

cis-4-[4-(4-Butylpiperazin-1-yl-3-spiro[2.5]oct-6-ylphenyl]-2,6-dimethylmorpholinehydrochloride

MS m/e (ESI) 440 (MH⁺).

cis-4-[4-(4-Cyclopropylmethylpiperazin-1-yl)-3-spiro[2.5]oct-6-ylphenyl]-2,6-dimethylmorpholinehydrochloride

MS m/e (ESI) 438 (MH⁺).

cis-2,6-Dimethyl-4-{3-spiro[2.5]oct-6-yl-4-[4-(tetrahydropyran-4-ylmethyl)piperazin-1-yl]phenyl}morpholinehydrochloride

MS m/e (ESI) 482 (MH⁺).

1-[4-(4-Methoxypiperidin-1-yl)-2-spiro[2.5]oct-6-ylphenyl]-4-pentylpiperazinehydrochloride

MS m/e (ESI) 454 (MH⁺).

1-Butyl-4-(2-cyclopent-1-enylphenyl)piperazine hydrochloride

MS m/e (ESI) 285 (MH⁺).

2-Methyl-1-{4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazin-1-yl}propan-2-olhydrochloride

MS m/e (ESI) 373 (MH⁺).

4-[2-(4,4-Dimethylcyclohex-1-enyl)phenyl]piperazine-1-carboxylic acidethyl ester

MS m/e (ESI) 343 (MH⁺).

1-{4-[2-(4,4-Dimethylcyclohex-1-enyl)phenyl]piperazin-1-yl}butan-1-one

MS m/e (ESI) 341 (MH⁺).

4-[4-(4-Butylpiperazin-1-yl)-3-cyclohex-1-enylphenyl]morpholinehydrochloride

MS m/e (ESI) 384 (MH⁺).

1-[2-(4,4-Dimethylcyclohexyl)phenyl]-4-(2-methoxyethyl)piperazinehydrochloride

MS m/e (ESI) 331 (MH⁺).

4-{3-(4-t-Butylcyclohexyl)-4-[4-(4,4,4-trifluorobutyl)piperazin-1-yl]phenyl}morpholinehydrochloride

MS m/e (ESI) 496 (MH⁺).

4-{3-(4-t-Butylcyclohex-1-enyl)-4-[4-(4,4,4-trifluorobutyl)piperazin-1-yl]phenyl}morpholinehydrochloride

MS m/e (ESI) 494 (MH⁺).

4-[3-(4-t-Butylcyclohexyl)-4-(4-isobutylpiperazine-1-yl)phenyl]morpholinehydrochloride

MS m/e (ESI) 442 (MH⁺).

4-[3-(4-t-Butylcyclohexyl)-4-(4-cyclohexylmethylpiperazin-1-yl)phenyl]morpholinehydrochloride

MS m/e (ESI) 482 (MH⁺).

4-{3-(4-t-Butylcyclohexyl)-4-[4-(2-ethylbutyl)piperazin-1-yl]phenyl}morpholinehydrochloride

MS m/e (ESI) 470 (MH⁺).

1-[4-(2-Spiro[2.5]oct-5-en-6-ylphenyl)piperazin-1-yl]butan-2-onehydrochloride

MS m/e (ESI) 339 (MH⁺).

4-[4-(4-Butylpiperazin-1-yl)-3-spiro[2.5]oct-6-ylphenyl]morpholinehydrochloride

MS m/e (ESI) 412 (MH⁺).

1-[2-(4,4-Dimethylcyclohexyl)-4-(4-ethoxypiperidin-1-yl)phenyl]-4-isobutylpiperazineehydrochloride

MS m/e (ESI) 456 (MH⁺).

1-Pentyl-4-(4-piperidin-1-yl-2-spiro[2.5]oct-6-ylphenyl)piperazinehydrochloride

MS m/e (ESI) 424 (MH⁺).

1-Isobutyl-4-(4-piperidin-1-yl-2-spiro[2.5]oct-6-ylphenyl)piperazinehydrochloride

MS m/e (ESI) 410 (MH⁺).

1-Cyclobutylmethyl-4-(4-piperidin-1-yl-2-spiro[2.5]oct-6-ylphenyl)piperazinehydrochloride

MS m/e (ESI) 422 (MH⁺).

1-[2-(4,4-Dimethylcyclohexyl)-4-(4-ethoxypiperidin-1-yl)phenyl]-4-(2-ethoxyethyl)piperazinehydrochloride

MS m/e (ESI) 472 (MH⁺).

1-[2-(4,4-Dimethylcyclohexyl)-4-(4-ethoxypiperidin-1-yl)phenyl]-4-(2-methoxyethyl)piperazinehydrochloride

MS m/e (ESI) 458 (MH⁺).

cis-2,6-Dimethyl-4-[4-(4-propylpiperazin-1-yl)-3-spiro[2.5]oct-6-ylphenyl]morpholinehydrochloride

MS m/e (ESI) 426 (MH⁺).

cis-4-[4-(4-Isobutylpiperazine-1-yl)-3-spiro[2.5]oct-6-ylphenyl]-2,6-dimethylmorpholinehydrochloride

MS m/e (ESI) 440 (MH⁺).

1-Isobutyl-4-[4-(4-methoxypiperidin-1-yl)-2-spiro[2.5]oct-6-ylphenyl]piperazinehydrochloride

MS m/e (ESI) 440 (MH⁺).

1-Cyclopropylmethyl-4-[4-(4-methoxypiperidin-1-yl)-2-spiro[2.5]oct-6-ylphenyl]piperazinehydrochloride

MS m/e (ESI) 438 (MH⁺).

1-4-[4-(4-Methoxypiperidin-1-yl)-2-spiro[2.5]oct-6-ylphenyl]-4-(tetrahydropyran-4-ylmethyl)piperazinehydrochloride

MS m/e (ESI) 482 (MH⁺).

1-(4-Bromo-2-spiro[2.5]oct-6-ylphenyl)-4-butylpiperazine

MS m/e (ESI) 405 (MH⁺).

1-Butyl-4-(2-cyclopentylphenyl)piperazine hydrochloride

MS m/e (ESI) 287 (MH⁺).

1-(2-Cyclopentylphenyl)-4-propylpiperazine hydrochloride

MS m/e (ESI) 273 (MH⁺).

1-(2-Cyclopentylphenyl)-4-cyclopropylmethylpiperazine hydrochloride

MS m/e (ESI) 285 (MH⁺).

1-[4-{2-(4-t-Butylcyclohexyl)phenyl}piperazin-1-yl]-2-cyclohexylethanone

MS m/e (ESI) 425 (MH⁺).

2-[4-{2-(4,4-Dimethylcyclohexyl)phenyl}piperazin-1-yl]cyclohexanonehydrochloride

MS m/e (ESI) 369 (MH⁺).

3-[4-{2-(4-t-Butylcyclohexyl)phenyl}piperazin-1-yl]piperidin-2-onehydrochloride

MS m/e (ESI) 398 (MH⁺).

2-{4-[2-(4-t-Butylcyclohexyl)phenyl}piperazin-1-yl]-N-(2-fluoroethyl)acetamidehydrochloride

MS m/e (ESI) 404 (MH⁺).

4-{3-(4-t-Butylcyclohexyl)-4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl}morpholinehydrochloride

MS m/e (ESI) 444 (MH⁺).

2-{4-[2-(4-t-Butylcyclohexyl)phenyl]piperazin-1-yl}-1-phenylethanolhydrochloride

MS m/e (ESI) 421 (MH⁺).

1-{4-[2-(4-t-Butylcyclohex-1-enyl)-4-morpholin-4-ylphenyl]piperazin-1-yl}butan-2-onehydrochloride

MS m/e (ESI) 454 (MH⁺).

4-[3-(4-t-Butylcyclohex-1-enyl)-4-(4-cyclopropylmethylpiperazin-1-yl)phenyl]morpholinehydrochloride

MS m/e (ESI) 438 (MH⁺).

1-Butyl-4-[2-(4-t-butylcyclohex-1-enyl)-4-(2,5-dimethylpyrrol-1-yl)phenyl]piperazinehydrochloride

MS m/e (ESI) 448 (MH⁺).

4-[3-(4-t-Butylcyclohexyl)-4-[4-[2-(tetrahydropyran-4-yl)ethyl]piperazin-1-yl]phenyl]morpholinehydrochloride

MS m/e (ESI) 498 (MH⁺).

1-[4-Bromo-2-(4-t-butylcyclohexyl)phenyl]-4-butylpiperazinehydrochloride

MS m/e (ESI) 435 (MH⁺).

4-[5-(4-t-Butylcyclohexyl)-4-(4-butylpiperazine-1-yl)-2-methoxyphenyl]morpholinehydrochloride

MS m/e (ESI) 472 (MH⁺).

4-[3-(4-t-Butylcyclohexyl)-4-[4-(2-ethylbutyl)piperazin-1-yl]phenyl]morpholinehydrochloride

MS m/e (ESI) 470 (MH⁺).

4-[3-(4-t-Butylcyclohex-1-enyl)-4-(4-isobutylpiperazine-1-yl)phenyl]morpholinehydrochloride

MS m/e (ESI) 440 (MH⁺).

1-[2-(4-t-Butylcyclohexyl)phenyl]-4-(3-methylbutyl)piperazinehydrochloride

MS m/e (ESI) 371 (MH⁺).

1-[2-(4-t-Butylcyclohexyl)phenyl]-4-(tetrahydropyran-4-ylmethyl)piperazinehydrochloride

MS m/e (ESI) 399 (MH⁺).

1-{2-(4-t-Butylcyclohexyl)phenyl}-4-(3-methylsulfonylpropyl)piperazinehydrochloride

MS m/e (ESI) 389 (MH⁺).

1-[2-(4-t-Butylcyclohexyl)phenyl]-4-thiophen-3-ylmethylpiperazinehydrochloride

MS m/e (ESI) 397 (MH⁺).

4-[5-(4-t-Butylcyclohexyl)-2-methoxy-4-[4-(tetrahydropyran-4-ylmethyl)piperazin-1-yl]phenyl]morpholinehydrochloride

MS m/e (ESI) 514 (MH⁺).

4-[3-(4-t-Butylcyclohexyl)-4-(4-butylpiperazin-1-yl)phenyl]-1-methylpiperazinedihydrochloride

MS m/e (ESI) 455 (MH⁺).

4-[4-(4-t-Butylcyclohexyl)-3-[4-(tetrahydropyran-4-ylmethyl)piperazin-1-yl]phenyl]morpholinehydrochloride

MS m/e (ESI) 484 (MH⁺).

4-[3-(4-t-Butylcyclohexyl)-4-(4-cyclopentylmethylpiperazin-1-yl)phenyl]morpholinehydrochloride

MS m/e (ESI) 468 (MH⁺).

4-[3-(4-t-Butylcyclohex-1-enyl)-4-(4-cyclopentylmethylpiperazin-1-yl)phenyl]morpholinehydrochloride

MS m/e (ESI) 466 (MH⁺).

1-[2-(4-t-Butylcyclohexyl)phenyl]-4-cyclopentylmethylpiperazinehydrochloride

MS m/e (ESI) 383 (MH⁺).

1-Butyl-4-[2-(4,4-dimethylcyclohexyl)-4-(4-methylpiperidin-1-yl)phenyl]piperazinehydrochloride

MS m/e (ESI) 426 (MH⁺).

1-[2-(4-t-Butylcyclohex-1-enyl)phenyl]-4-pentylpiperazine hydrochloride

MS m/e (ESI) 369 (MH⁺).

1-Butyl-4-[2-(4-t-butylcyclohex-1-enyl)-5-pyrrolidin-1-ylphenyl]piperazinehydrochloride

MS m/e (ESI) 424 (MH⁺).

1-Butyl-4-[2-(4-t-butylcyclohexyl)-5-pyrrolidin-1-ylphenyl]piperazinehydrochloride

MS m/e (ESI) 426 (MH⁺).

1-Butyl-4-[2-(4,4-dimethylcyclohexyl)-4-(3,3-dimethylpiperidin-1-yl)phenyl]piperazinehydrochloride

MS m/e (ESI) 440 (MH⁺).

1-(2-Spiro[5.5]undec-2-en-3-ylphenyl)-4-(tetrahydropyran-4-ylmethyl)piperazinehydrochloride

MS m/e (ESI) 409 (MH⁺).

1-Cyclopropylmethyl-4-[2-(4,4-dimethylcyclohex-1-enyl)-4-(4-methoxypiperidin-1-yl)phenyl]piperazinehydrochloride

MS m/e (ESI) 438 (MH⁺).

1-[2-(4,4-Dimethylcyclohex-1-enyl)-4-(4-methoxypiperidin-1-yl)phenyl]-4-furan-2-ylmethylpiperazinehydrochloride

MS m/e (ESI) 464 (MH⁺).

N-Ethyl-2-[4-[4-(4-methoxypiperidin-1-yl)-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazin-1-yl]acetamidehydrochloride

MS m/e (ESI) 499 (MH⁺).

[4-[2-(4,4-Diethylcyclohexyl)phenyl]piperazin-1-yl]morpholin-4-ylmethanone

MS m/e (ESI) 414 (MH⁺).

1-[4-(4-Propylpiperazin-1-yl)-3-(3,3,1,5,5-tetramethylcyclohexyl)phenyl]azepanehydrochloride

MS m/e (ESI) 440 (MH⁺).

1-[4-(4-Butylpiperazin-1-yl)-3-(4,4-dimethylcyclohexyl)phenyl]azocanehydrochloride

MS m/e (ESI) 440 (MH⁺).

1-[2-(4,4-Dimethylcyclohexyl)-4-piperidin-1-ylphenyl]-4-furan-3-ylmethylpiperazinehydrochloride

MS m/e (ESI) 436 (MH⁺).

1-[4-{2-(4-Ethylcyclohex-3-enyl)-4-morpholin-4-ylphenyl}piperazin-1-yl]butan-2-onehydrochloride

MS m/e (ESI) 426 (MH⁺).

1-[4-(4-Bromopiperidin-1-yl)-2-(4,4-dimethylcyclohexyl)phenyl]-4-propylpiperazinehydrochloride

MS m/e (ESI) 504 (MH⁺).

1-Cyclopropylmethyl-4-[4-fluoro-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 373 (MH⁺).

1-Cyclopropylmethyl-4-[4-[1,3,4]oxadiazol-2-yl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 421 (MH⁺).

1-Cyclohexylmethyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 397 (MH⁺).

1-(2-Ethylbutyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 385 (MH⁺).

1-[5-[1,3,4]Oxadiazol-2-yl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]-4-propylpiperazinehydrochloride

MS m/e (ESI) 409 (MH⁺).

1-Methyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 315 (MH⁺).

1-Ethyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 329 (MH⁺).

1-Pyridin-4-ylmethyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 392 (MH⁺).

3-(4-Propylpiperazin-1-yl)-4-(3,3,5,5-tetramethylcyclohexyl)phenolhydrochloride

MS m/e (ESI) 359 (MH⁺).

3-(4-Butylpiperazin-1-yl)-4-(3,3,5,5-tetramethylcyclohexyl)phenolhydrochloride

MS m/e (ESI) 373 (MH⁺).

3-(4-Cyclopropylmethylpiperazin-1-yl)-4-(3,3,5,5-tetramethylcyclohexyl)phenolhydrochloride

MS m/e (ESI) 371 (MH⁺).

1-Cyclopropylmethyl-4-[4-(6-methoxypyridin-2-yl)-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinedihydrochloride

MS m/e (ESI) 462 (MH⁺).

2-[4-[2-(3,3,5,5-Tetramethylcyclohexyl)phenyl]piperazin-1-ylmethyl]cyclopropanecarboxylicacid hydrochloride

MS m/e (ESI) 399 (MH⁺).

1-(2-Methanesulfonylethyl)-4-{2-(3,3,5,5-tetramethylcyclohexyl)phenyl}piperazinehydrochloride

MS m/e (ESI) 407 (MH⁺).

1-Cyclopropylmethyl-4-[2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]-[4]diazepanehydrochloride

MS m/e (ESI) 367 (MH⁺).

1-[2-(3,3,5,5-Tetramethylcyclohexyl)phenyl]-4-(3,3,3-trifluoropropyl)piperazinehydrochloride

MS m/e (ESI) 397 (MH⁺).

Methyl-[2-[4-{2-(3,3,5,5-tetramethylcyclohexyl)phenyl}piperazin-1-yl]ethyl]aminedihydrochloride

MS m/e (ESI) 358 (MH⁺).

Dimethyl-{2-[4-{2-(3,3,5,5-tetramethylcyclohexyl)phenyl}piperazin-1-yl]ethyl}aminedihydrochloride

MS m/e (ESI) 372 (MH⁺).

2-Propyl-5-[2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]-2,5-diazabicyclo[2.2.1]heptanehydrochloride

MS m/e (ESI) 353 (MH⁺).

2-Cyclopropylmethyl-5-[2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]-2,5-diazabicyclo[2.2.1]heptanehydrochloride

MS m/e (ESI) 365 (MH⁺).

1-{4-[2-(3,3,5,5-Tetramethylcyclohexyl)phenyl]piperazin-1-ylmethyl}cyclopropanolhydrochloride

MS m/e (ESI) 371 (MH⁺).

1-(Tetrahydropyran-4-yl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 385 (MH⁺).

1-[4-Fluoromethyl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-propylpiperazinehydrochloride

MS m/e (ESI) 375 (MH⁺).

1-(Tetrahydropyran-4-ylmethyl)-4-[2-(3,3,4,4-tetramethylcyclopent-1-enyl)phenyl]piperazinehydrochloride

MS m/e (ESI) 383 (MH⁺).

2-[4-[2-(4-t-Butylcyclohexyl)phenyl]piperazin-1-yl]-N-pyridin-2-ylacetamidedihydrochloride

MS m/e (ESI) 435 (MH⁺).

Test Example 1 Evaluation of Compounds in Jurkat Cell Adhesion System

<Immobilization of Human Fibronectin in 96-Well Plate>

Human fibronectin (Becton Dickinson Biosciences) was diluted withphosphate-buffered saline (hereinafter abbreviated as PBS; Sigma) to0.1-0.01 μg/ml, and the diluted solution was added to a 96-well plate(Becton Dickinson) at 50μ/well, and allowed to stand overnight at 4° C.On the following day, the supernatant was removed from the plate, andthen PBS containing 1% bovine serum albumin (hereinafter abbreviated asBSA; Sigma) was added thereto at 100 μl/well and incubation wasperformed at 37° C. for 2 hours in a CO₂ incubator (Hirasawa).

<Adhesion Assay>

The supernatant was removed from each plate and Jurkat cells suspendedin RPMI-1640 (Sigma) containing 1 mg/ml BSA were added at 80 μl/well for2.5×10⁵ cells/well. The compound diluted to different concentrationswith RPMI-1640 containing 1 mg/ml BSA was immediately added at 10μl/well, and then 100 nM phorbol myristate acetate (hereinafterabbreviated as PMA; Sigma) in RPMI-1640 containing 1 mg/ml BSA was addedat 10 μl/well and the plate was incubated in a CO₂ incubator at 37° C.for 45-60 minutes. The supernatant was removed from the plate and eachwell was washed several times with 100 μl/well of RPMI-1640, after which50 mM citrate buffer (pH 5.0) containing 3.75 mMp-nitrophenol-N-acetyl-β-D-glucosaminide (Sigma) and 0.25% Triton X-100(Sigma) were added at 60 μl/well, and the mixture was placed in a CO₂incubator and incubated at 37° C. for 45 minutes. After incubation, 50mM glycine buffer (pH 10.4) containing 5 mM EDTA was added at 90μl/well, and the absorbance at 405 nm was measured with an EL340Automated Microplate Reader (BIO-TEK) to determine the adhered cellcount. The concentration of each compound which inhibited the increasein the number of adhered cells by the PMA-stimulation by 50% wasrecorded as the IC50 (μM).

TABLE 1 Example IC50 (μM) 1 4.5 7 2.5 8 2.2 9 3.1 10 4.7 12 3.1 13 3.914 4.9 15 2.3 17 6.1 18 2.6 19 6.2 20 7.7 22 2.2 28 3.1 30 5.5 31 4.5 323.6 47 5.0 48 7.9 69 3.6 85 6.4 103 4.5 117 4.7

Test Example 2 Evaluation of Compounds in Human Peripheral BloodNeutrophil Adhesion System

<Preparation of Human Peripheral Blood Neutrophils>

To a plastic centrifugation tube containing 100 units of heparin sodium(Shimizu Pharmaceutical) was added 25 ml of fresh blood sampled from ahealthy human. After adding and mixing therewith 8 ml of physiologicalsaline (Otsuka Pharmaceutical) containing 6% Dextran (Nacalai), themixture was allowed to stand room temperature for 45 minutes forsedimentation of the erythrocytes. The resultant supernatant wastransferred to another plastic centrifugation tube and combined with anequivalent volume of phosphate-buffered saline (hereinafter abbreviatedas PBS; Sigma), and then centrifuged at 1600 rpm for 7 minutes at roomtemperature. The obtained hematocyte fraction was suspended in 4 ml ofPBS, and the suspension was superposed on 4 ml of Ficoll-Paque™ PLUS(Amersham Biosciences). The resultant bilayer liquid was centrifuged at2000 rpm for 30 minutes at room temperature, after which the supernatantwas removed and the precipitate was suspended in 10 ml of PBS andcentrifuged at 1200 rpm for 7 minutes, and the supernatant was removed.The resulting precipitate was suspended in 0.5 ml of PBS again, and then10 ml of distilled water (Otsuka Pharmaceutical) was added, 0.5 ml of anaqueous solution containing 3 M NaCl was immediately added to restoreisotonicity, the mixture was centrifuged at 1200 rpm for 7 minutes, andthe obtained precipitate was suspended in PBS containing 1 mg/ml bovineserum albumin (hereinafter abbreviated as BSA; Sigma) again and storedin ice until being used for the experiment.

<Fluorescent Labeling of Human Peripheral Blood Neutrophils>

The obtained neutrophils were suspended in PBS containing 1 mg/ml BSA at2×10⁷ cells/ml. BCECF-AM (Dojin) was added to a final concentration of 5μM, and the mixture was incubated at 37° C. for 45 minutes. It was thenrinsed twice with PBS containing 1 mg/ml BSA by centrifugation,suspended again in PBS containing 1 mg/ml BSA at 5×10⁷ cells/ml, andstored in ice until use.

<Preparation of HUVEC Immobilized Plate>

Human umbilical vein endothelial cells (hereinafter abbreviated asHUVEC) were suspended in MCDB131 medium (Chlorella Industries)containing 10% fetal calf serum and 30 μg/ml endothelial cell growthsupplement (Becton Dickinson Bioscience). The suspension was added at7.5×10³ cells/well to a 96-well plate (Iwaki) immobilized with type Icollagen, and cultured for 3 days in a CO₂ incubator (Hirasawa). Uponconfirming confluency of the cells, the supernatant was discarded, theplate was rinsed twice with PBS, and then PBS containing 0.1%glutaraldehyde (Kanto Kagaku) was added at 100 μl/well and the HUVECswere immobilized for 5 minutes. The supernatant was discarded and theplate was washed twice with PBS, and then PBS was added at 100 μl/welland the mixture was stored at 4° C. until use.

<Adhesion Assay>

To 6.5 ml of RPMI-1640 medium (Sigma) containing 1 mg/ml of BSA wereadded 0.5 ml of a suspension of BCECF-AM labeled neutrophils at 5×10⁷/mlstored in ice, which was mixed, and the mixture was added at 80 μl/wellto a HUVEC immobilized plate. To this plate were immediately added 10μl/well of a solution of the compound diluted at differentconcentrations with RPMI-1640 containing 1 mg/ml BSA, and 10 μl/well of100 nM phorbol myristate acetate (hereinafter abbreviated as PMA; Sigma)in RPMI-1640 containing 1 mg/ml BSA, and the mixture was incubated in aCO₂ incubator at 37° C. for 45 minutes. The supernatant was removed fromthe plate, which was then washed several times with RPMI-1640 at 100μl/well, and then PBS containing 0.1% NP-40 (Calbiochem) was addedthereto at 100 μl/well and the fluorescent intensity was measured withan ARVO™SX 1420 multi label counter (Wallac) to determine the number ofadhered cells. The concentration of each compound which inhibited theincrease in the number of adhered cells by the PMA-stimulation by 50%was recorded as the IC50 (μM).

TABLE 2 Example IC50 (μM) 1 9.1 7 9.8 8 22.5 9 6.7 10 15.6 12 18.3 1353.9 14 19.7 15 21.0 17 17.9 18 12.1 19 11.6 20 6.1 22 18.1 28 8.5 3016.9 31 9.5 32 7.0 47 11.8 48 4.9 69 9.4 85 16.4 103 19.3 117 7.1

Test Example 3 Evaluation of Compounds in Oxazolone-Induced ColonNeutrophil Infiltration Model

<Sensitization with Oxazolone>

Five- to six-week-old male Balb/c mice (Charles River Japan) were shavenat the abdomen to an approximately 2 cm square area. A 100% ethanolsolution containing 3% 4-ethoxymethylene-2-phenyl-2-oxazolin-5-one(hereinafter referred to as “oxazolone”; Sigma) was applied at 150 μlonto the abdomen of each mouse.

<Preparation of Emulsion Containing Oxazolone>

Distilled water (Otsuka Pharmaceutical) was added in an equivalentvolume to 100% peanut oil (Kanto Kagaku) containing 1% oxazolone, andthe components were vigorously mixed with a glass syringe (Top Co.), toprepare an emulsion containing 0.5% oxazolone.

<Induction with Oxazolone>

The mice were fasted on the 3rd day after oxazolone sensitization, andwere injected with 100 μl of the emulsion containing 0.5% oxazoloneprepared in the way described above intrarectally at a siteapproximately 3 cm from the anus under ether anesthesia on the 4th day.

<Colon-Infiltrating Neutrophil Assay>

Each compound was suspended or dissolved in an aqueous solutioncontaining 0.5% methyl cellulose (Wako), and orally administered at 30mg/kg 30 minutes prior to the intrarectal injection of oxazoloneemulsion. Four hours after the intrarectal injection of oxazolone, micewere sacrificed by cervical dislocation, and colons were extirpated,dissected in the longitudinal direction, washed with physiologicalsaline, and transferred to ice-cooled plastic centrifugation tubes.After adding 1 ml of 50 mM potassium phosphate buffer (hereinafterabbreviated as KPB) (pH 6.0) to the tube, and the tissue werehomogenized with PHYSCOTRON (Microtec Nition Co., Ltd.), 2 ml of 50 mMKPB (pH 6.0) was added and the mixture was centrifuged at 3000 rpm, 4°C. for 10 minutes and the supernatant was removed. To the resultantprecipitate was added 1 ml of 50 mM KPB (pH 6.0) containing 0.5%hexadecyltrimethyl-ammonium bromide (Sigma), and freeze-thawed 3 to 5times using liquid nitrogen and hot water, centrifuged at 3000 rpm, 4°C. for 10 minutes to yield a supernatant. The myeloperoxidase enzymeactivity in the supernatant was assayed in the following manner.Specifically, to 10 μl of the obtained supernatant was added 200 μl of50 mM KPB (pH6.0) containing 0.017% o-dianisidine (Sigma) and 0.0005%hydrogen peroxide (Wako), incubated at 37° C., and the change inabsorbance at 450 nm was continuously measured for 1 minute using anEL340 Automated Microplate Reader (BIO-TEK) in kinetic mode. The unitswere the rate of change in absorbance per minute (mO.D./min.). Withregard to the effect of each compound, the inhibitory rate (%) withrespect to the oxazolone control group, i.e. theoxazolone-injected/compound-free group, was shown in the table 3.

TABLE 3 Inhibitory rate Example (%) 1 45 7 37 8 22 9 35 10 73 12 34 1313 14 64 15 40 17 30 18 50 19 53 20 38 22 28 28 48 30 23 31 38 32 51

Test Example 4 Evaluation of Compounds in DSS-Induced Colitis Model

A 1-3% solution of dextran sulfate sodium (hereinafter abbreviated asDSS; ICN) in purified water (Otsuka Pharmaceutical) was fed freely to 6-to 7-week-old male Balb/c mice (Charles River Japan) for 5-7 days toinduce colitis. Disease Activity Index (hereinafter abbreviated as DAI)scored based on fecal hardness, blood content in feces and body weightchange, the number of neutrophils infiltrating the colon and the lengthof the colon were used as indexes to evaluate compounds. Each compoundwas suspended or dissolved in an aqueous solution containing 0.5% methylcellulose (Wako), and orally administered at 30 mg/kg once a day, for5-7 successive days. The compounds of Examples 1, 7, 8, 9, 10, 12, 13,14, 15, 17, 18, 19, 20, 22, 28, 30, 31, 32 and 34 exhibited particularlygood improvement in comparison with the DSS control group, i.e. the DSSwater-loaded/compound-free group.

INDUSTRIAL APPLICABILITY

The compounds of the invention have excellent cell adhesion inhibitoryaction or cell infiltration inhibitory action, and can therefore serveas pharmaceuticals which are useful as therapeutic or prophylacticagents for various inflammatory diseases and autoimmune diseasesassociated with adhesion and infiltration of leukocytes, such asinflammatory bowel disease (particularly ulcerative colitis or Crohn'sdisease), irritable bowel syndrome, rheumatoid arthritis, psoriasis,multiple sclerosis, asthma and atopic dermatitis.

1. A compound represented by the following general formula, a saltthereof or a hydrate of the foregoing:

wherein R10 represents 5- to 10-membered cycloalkyl optionallysubstituted with a substituent selected from Group A1 or 5- to10-membered cycloalkenyl optionally substituted with a substituentselected from Group A1, R20, R21, R22 and R23 may be the same ordifferent and each represents hydrogen, hydroxyl, halogen, cyano, C2-7alkylcarbonyl, nitro, amino, mono(C1-6 alkyl)amino, di(C1-6 alkyl)amino,C1-6 alkyl optionally substituted with a substituent selected from GroupB1, C1-6 alkoxy optionally substituted with a substituent selected fromGroup B1, a 4- to 8-membered heterocyclic group optionally substitutedwith a substituent selected from Group C1 or a 5- to 10-memberedheteroaryl ring group optionally substituted with a substituent selectedfrom Group C1, R30, R31 and R32 may be the same or different and eachrepresents hydrogen, hydroxyl, halogen, cyano, carboxyl, C1-6 alkyl,C1-6 alkoxy or C2-7 alkoxycarbonyl, or two of R30, R31 and R32 bondtogether to form oxo (═O) or methylene (—CH₂—) and the other representshydrogen, hydroxyl, halogen, cyano, carboxyl, C1-6 alkyl, C1-6 alkoxy orC2-7 alkoxycarbonyl, R40 represents C1-10 alkyl optionally substitutedwith a substituent selected from Group D1,3- to 8-membered cycloalkyloptionally substituted with a substituent selected from Group E1, a 4-to 8-membered heterocyclic group optionally substituted with asubstituent selected from Group E1, C2-7 alkenyl optionally substitutedwith a substituent selected from Group F1, C2-7 alkynyl optionallysubstituted with a substituent selected from Group F1, C2-7alkylcarbonyl optionally substituted with a substituent selected fromGroup G1, mono(C1-6 alkyl)aminocarbonyl, 4- to 8-membered heterocycliccarbonyl, C2-7 alkoxycarbonyl or C1-6 alkylsulfonyl, n represents aninteger of 0, 1 or 2, and X1 represents CH or nitrogen, wherein Group A1consists of hydroxyl, halogen, cyano, C1-6 alkoxy, C1-6 alkyl, C1-6haloalkyl, C2-7 alkylene, and phenyl optionally substituted with asubstituent selected from Group C1, C1-6 alkyl, C1-6 haloalkyl and C2-7alkylene, where C2-7 alkylene is permissible only in the case that aspiro union is formed together with the substituted 5- to 10-memberedcycloalkyl or the substituted 5- to 10-membered cycloalkenyl, Group B1consists of halogen, C2-7 alkoxycarbonyl and carboxyl, Group C1 consistsof cyano, halogen, C1-6 alkyl and C1-6 alkoxy, Group D1 consists ofhydroxyl, halogen, cyano, C1-6 alkoxy, C1-6 alkylthio, C1-6alkylsulfonyl, C1-6 alkylsulfinyl, mono(C1-6 alkyl)amino, di(C1-6alkyl)amino, C2-7 alkylcarbonylamino, 3- to 8-membered cycloalkyloptionally substituted with a substituent selected from Group H1, C2-7alkoxycarbonyl, carboxyl, a 4- to 8-membered heterocyclic group, a 5- to10-membered heteroaryl ring group, a 6- to 10-membered aryl ring group,C2-7 alkylcarbonyl, a 6- to 10-membered aryl ring carbonyl group,aminocarbonyl, mono(C 1-6 alkyl)aminocarbonyl optionally substitutedwith halogen, mono(3- to 8-membered cycloalkyl)aminocarbonyl, mono(C2-7alkoxyalkyl)aminocarbonyl, di(C 1-6 alkyl)aminocarbonyl, mono(5- to10-membered heteroaryl ring)aminocarbonyl, 4- to 8-membered heterocycliccarbonyl optionally substituted with C1-6 alkyl, and 5- to 10-memberedheteroaryl ring carbonyl, Group E1 consists of halogen, C1-6 alkoxy, oxo(═O) and C1-6 alkyl, Group F1 consists of halogen and C1-6 alkoxy, GroupG1 consists of 3- to 8-membered cycloalkyl, and Group H1 consists ofhydroxyl, C1-6 haloalkyl, C1-6 alkyl, C2-7 alkoxyalkyl, mono(C1-6alkyl)aminocarbonyl, di(C1-6 alkyl)aminocarbonyl, C2-7 alkoxycarbonyl,carboxyl and C2-7 cyanoalkyl, with the proviso that a compoundrepresented by the formula

is excepted.
 2. A compound represented by the following general formula,a salt thereof or a hydrate of the foregoing:

wherein R10 represents 5- to 10-membered cycloalkyl optionallysubstituted with a substituent selected from Group A1 or 5- to10-membered cycloalkenyl optionally substituted with a substituentselected from Group A1, R20, R21, R22 and R23 may be the same ordifferent and each represents hydrogen, hydroxyl, halogen, cyano, C2-7alkylcarbonyl, nitro, amino, mono(C1-6 alkyl)amino, di(C1-6 alkyl)amino,C1-6 alkyl optionally substituted with a substituent selected from GroupB1, C1-6 alkoxy optionally substituted with a substituent selected fromGroup B1, a 4- to 8-membered heterocyclic group optionally substitutedwith a substituent selected from Group C1 or a 5- to 10-memberedheteroaryl ring group optionally substituted with a substituent selectedfrom Group C1, R30, R31 and R32 may be the same or different and eachrepresents hydrogen, hydroxyl, halogen, cyano, carboxyl, C1-6 alkyl,C1-6 alkoxy or C2-7 alkoxycarbonyl, or two of R30, R31 and R32 bondtogether to form oxo (═O) or methylene (—CH₂—) and the other representshydrogen, hydroxyl, halogen, cyano, carboxyl, C1-6 alkyl, C1-6 alkoxy orC2-7 alkoxycarbonyl, R40 represents C1-10 alkyl optionally substitutedwith a substituent selected from Group D1,3- to 8-membered cycloalkyloptionally substituted with a substituent selected from Group E1, a 4-to 8-membered heterocyclic group optionally substituted with asubstituent selected from Group E1, C2-7 alkenyl optionally substitutedwith a substituent selected from Group F1, C2-7 alkynyl optionallysubstituted with a substituent selected from Group F1, C2-7alkylcarbonyl optionally substituted with a substituent selected fromGroup G1, mono(C1-6 alkyl)aminocarbonyl, 4- to 8-membered heterocycliccarbonyl, C2-7 alkoxycarbonyl or C1-6 alkylsulfonyl, n represents aninteger of 0, 1 or 2, and wherein Group A1 consists of hydroxyl,halogen, cyano, C1-6 alkoxy, C1-6 alkyl, C1-6 haloalkyl, C2-7 alkylene,and phenyl optionally substituted with a substituent selected from GroupC1, C1-6 alkyl, C1-6 haloalkyl and C2-7 alkylene, where C2-7 alkylene ispermissible only in the case that a spiro union is formed together withthe substituted 5- to 10-membered cycloalkyl or the substituted 5- to10-membered cycloalkenyl, Group B1 consists of halogen, C2-7alkoxycarbonyl and carboxyl, Group C1 consists of cyano, halogen, C1-6alkyl and C1-6 alkoxy, Group D1 consists of hydroxyl, halogen, cyano,C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylsulfonyl, C1-6 alkylsulfinyl,mono(C1-6 alkyl)amino, di(C1-6 alkyl)amino, C2-7 alkylcarbonylamino, 3-to 8-membered cycloalkyl optionally substituted with a substituentselected from Group H1, C2-7 alkoxycarbonyl, carboxyl, a 4- to8-membered heterocyclic group, a 5- to 10-membered heteroaryl ringgroup, a 6- to 10-membered aryl ring group, C2-7 alkylcarbonyl, a 6- to10-membered aryl ring carbonyl group, aminocarbonyl, mono(C1-6alkyl)aminocarbonyl optionally substituted with halogen, mono(3- to8-membered cycloalkyl)aminocarbonyl, mono(C2-7alkoxyalkyl)aminocarbonyl, di(C1-6 alkyl)aminocarbonyl, mono(5- to10-membered heteroaryl ring)aminocarbonyl, 4- to 8-membered heterocycliccarbonyl optionally substituted with C1-6 alkyl, and 5- to 10-memberedheteroaryl ring carbonyl, Group E1 consists of halogen, C1-6 alkoxy, oxo(═O) and C1-6 alkyl, Group F1 consists of halogen and C1-6 alkoxy, GroupG1 consists of 3- to 8-membered cycloalkyl, and Group H1 consists ofhydroxyl, C1-6 haloalkyl, C1-6 alkyl, C2-7 alkoxyalkyl, mono(C1-6alkyl)aminocarbonyl, di(C1-6 alkyl)aminocarbonyl, C2-7 alkoxycarbonyl,carboxyl and C2-7 cyanoalkyl.
 3. The compound according to claim 1 or 2,the salt thereof or the hydrate of the foregoing, wherein R10 represents5- to 10-membered cycloalkyl optionally substituted with a substituentselected from Group A2, or 5- to 10-membered cycloalkenyl optionallysubstituted with a substituent selected from Group A2, wherein Group A2consists of hydroxyl, phenyl, C1-6 alkyl, C1-6 haloalkyl and C2-7alkylene, where C2-7 alkylene is permissible only in the case that aspiro union is formed together with the substituted 5- to 10-memberedcycloalkyl or the substituted 5- to 10-membered cycloalkenyl.
 4. Thecompound according to claim 1 or 2, the salt thereof or the hydrate ofthe foregoing, wherein R10 represents 5- to 10-membered cycloalkyloptionally substituted with hydroxyl, phenyl, C1-6 alkyl, C1-6haloalkyl, 1,2-ethylene, trimethylene, tetramethylene or pentamethylene,or 5- to 10-membered cycloalkenyl optionally substituted with hydroxyl,phenyl, C1-6 alkyl, C1-6 haloalkyl, 1,2-ethylene, trimethylene,tetramethylene or pentamethylene, where 1,2-ethylene, trimethylene,tetramethylene or pentamethylene is permissible only in the case that aspiro union is formed together with the substituted 5- to 10-memberedcycloalkyl or the substituted 5- to 10-membered cycloalkenyl.
 5. Thecompound according to claim 1 or 2, the salt thereof or the hydrate ofthe foregoing, wherein R10 represents cyclohexyl, 4-t-butylcyclohexyl,4,4-dimethylcyclohexyl, 4,4-diethylcyclohexyl,3,3,5,5-tetramethylcyclohexyl, 3,5-dimethylcyclohexyl,4-phenylcyclohexyl, 4-trifluoromethylcyclohexyl, 4-n-butylcyclohexyl,cyclopentyl, 3,3,4,4-tetramethylcyclopentyl, cycloheptyl, cyclooctyl ora group represented by the formula:

wherein s represents an integer of 0, 1, 2 or
 3. 6. The compoundaccording to claim 1 or 2, the salt thereof or the hydrate of theforegoing, wherein R20, R21, R22 and R23 may be the same or differentand each represents hydrogen, hydroxyl, halogen, cyano, C2-7alkylcarbonyl, nitro, amino, mono(C1-6 alkyl)amino, di(C1-6 alkyl)amino,C1-6 alkyl optionally substituted with a substituent selected from GroupB1, C1-6 alkoxy optionally substituted with a substituent selected fromGroup B1, a 4- to 8-membered heterocyclic group optionally substitutedwith a substituent selected from Group C1 or a 5- to 6-memberedheteroaryl ring group optionally substituted with a substituent selectedfrom Group C1.
 7. The compound according to claim 1 or 2, the saltthereof or the hydrate of the foregoing, wherein R20, R21, R22 and R23may be the same or different and each represents hydrogen, hydroxyl,halogen, cyano, acetyl, nitro, amino, monomethylamino, monoethylamino,dimethylamino, C1-6 alkyl optionally substituted with a substituentselected from Group B1, C1-6 alkoxy optionally substituted with asubstituent selected from Group B1, a 4- to 8-membered heterocyclicgroup optionally substituted with a substituent selected from Group C1,where the 4- to 8-membered heterocyclic group is derived by eliminatinghydrogen linked to nitrogen of a 4- to 8-membered heterocycle, or a 5-to 6-membered heteroaryl ring group optionally substituted with asubstituent selected from Group C2, wherein Group C2 consists of C1-6alkoxy and C1-6 alkyl.
 8. The compound according to claim 1 or 2, thesalt thereof or the hydrate of the foregoing, wherein R20, R21, R22 andR23 may be the same or different and each represents hydrogen, halogen,cyano, acetyl, monomethylamino, monoethylamino, dimethylamino, methyl,methoxy, ethoxy, morpholin-4-yl optionally substituted with asubstituent selected from Group C2, piperidin-1-yl optionallysubstituted with a substituent selected from Group C2, pyrrolidin-1-yloptionally substituted with a substituent selected from Group C2,azetidin-1-yl, pyridin-2-yl or pyridin-3-yl.
 9. The compound accordingto claim 1 or 2, the salt thereof or the hydrate of the foregoing,wherein at least two of R20, R21, R22 and R23 are hydrogen, and theremaining groups, which may be the same or different, are hydrogen,halogen, cyano, acetyl, monomethylamino, monoethylamino, dimethylamino,methyl, methoxy, ethoxy, morpholin-4-yl optionally substituted with asubstituent, selected from Group C2, piperidin-1-yl optionallysubstituted with a substituent selected from Group C2, pyrrolidin-1-yloptionally substituted with a substituent selected from Group C2,azetidin-1-yl, pyridin-2-yl or pyridin-3-yl.
 10. The compound accordingto claim 1 or 2, the salt thereof or the hydrate of the foregoing,wherein three of R20, R21, R22 and R23 are hydrogen, and the remaininggroup is hydrogen, fluorine, cyano, dimethylamino, methyl, methoxy,morpholin-4-yl optionally substituted with a substituent selected fromGroup C3, piperidin-1-yl optionally substituted with a substituentselected from Group C3 or pyrrolidin-1-yl optionally substituted with asubstituent selected from Group C3, wherein Group C3 consists ofmethoxy, ethoxy and methyl.
 11. The compound according to claim 1 or 2,the salt thereof or the hydrate of the foregoing, wherein R30, R31 andR32 may be the same or different and each represents hydrogen or C1-6alkyl, or R30 and R31 bond together to form oxo (═O) and R32 representshydrogen or C1-6 alkyl.
 12. The compound according to claim 1 or 2, thesalt thereof or the hydrate of the foregoing, wherein R30, R31 and R32may be the same or different and each represents hydrogen or methyl, orR30 and R31 bond together to form oxo (═O) and R32 represents hydrogenor methyl.
 13. The compound according to claim 1 or 2, the salt thereofor the hydrate of the foregoing, wherein all of R30, R31 and R32represent hydrogen.
 14. The compound according to claim 1 or 2, the saltthereof or the hydrate of the foregoing, wherein R40 represents C1-6alkyl optionally substituted with a substituent selected from Group D1,3- to 8-membered cycloalkyl optionally substituted with a substituentselected from Group E1, C2-7 alkenyl, C2-7 alkynyl or C2-7alkylcarbonyl.
 15. The compound according to claim 1 or 2, the saltthereof or the hydrate of the foregoing, wherein R40 represents C1-6alkyl optionally substituted with a substituent selected from Group D2,wherein Group D2 consists of hydroxyl, halogen, cyano, C1-6 alkoxy, 3-to 8-membered cycloalkyl, a 4- to 8-membered heterocyclic group,mono(C1-6 alkyl)aminocarbonyl, di(C1-6 alkyl)aminocarbonyl, C2-7alkylcarbonyl, a 5-membered heteroaryl ring group, 4- to 8-memberedheterocyclic carbonyl or phenyl.
 16. The compound according to claim 1or 2, the salt thereof or the hydrate of the foregoing, wherein R40represents n-propyl, n-butyl, n-pentyl, isobutyl, ethylcarbonylmethyl,methoxyethyl, ethoxyethyl, cyclopropylmethyl ortetrahydropyran-4-ylmethyl.
 17. The compound according to claim 1 or 2,the salt thereof or the hydrate of the foregoing, wherein n representsan integer of .
 18. The compound according to claim 1, the salt thereofor the hydrate of the foregoing, wherein X1 represents nitrogen.
 19. Thecompound according to claim 1 or 2, the salt thereof or the hydrate ofthe foregoing, selected from the compound group consisting of1-[2-(4,4-dimethylcyclohexyl)-5-methoxyphenyl]-4-pentylpiperazine,1-butyl-4-[2-(4-t-butylcyclohex-1-enyl)-4-(4-methoxypiperidin-1-yl)phenyl]piperazine,1-butyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine,2-{4-[2-(4-t-butylcyclohexyl)phenyl]piperazin-1-yl}-N-ethylacetamide,cis-4-(4-t-butylcyclohexyl)-3-(4-butylpiperazin-1-yl)benzonitrile,trans-4-(4-t-butylcyclohexyl)-3-(4-butylpiperazin-1-yl)benzonitrile,1-butyl-4-(2-cyclohexylphenyl)piperazine,1-butyl-4-[2-(4-t-butylcyclohexyl)phenyl]piperazine,1-{4-[2-(4,4-dimethylcyclohexyl)phenyl]piperazin-1-yl}butan-2-one,4-[3-(4-t-butylcyclohex-1-enyl)-4-(4-butylpiperazin-1-yl)phenyl]morpholine,1-[2-(4-t-butylcyclohexyl)phenyl]-4-(2-methoxyethyl)piperazine,1-[2-(4-t-butylcyclohex-1-enyl)-4-(4-methoxypiperidin-1-yl)phenyl]-4-cyclopropylmethylpiperazine,1-(tetrahydropyran-4-ylmethyl)-4-[2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazine,4-[4-(4-propylpiperazin-1-yl)-3-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]morpholine,1-{4-[2-(4,4-diethylcyclohex-1-enyl)-4-morpholin-4-ylphenyl]piperazin-1-yl}butan-2-one,1-propyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine,1-butyl-4-[4-(4-methoxypiperidin-1-yl)-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine,1-butyl-4-[2-(3,5-dimethylcyclohexyl)phenyl]piperazine,1-[2-(4,4-diethylcyclohexyl)phenyl]-4-(tetrahydropyran-4-ylmethyl)piperazine,4-[4-(4-butylpiperazin-1-yl)-3-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]morpholine,4-[4-(4-butylpiperazin-1-yl)-3-(3,3,5,5-tetramethylcyclohexyl)phenyl]morpholine,1-[4-(4-ethoxypiperidin-1-yl)-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-propylpiperazine,cis-4-[4-(4-butylpiperazin-1-yl)-3-(4,4-dimethylcyclohexyl)phenyl]-2,6-dimethylmorpholine,4-{4-(4-pentylpiperazin-1-yl)-3-spiro[2.5]oct-6-ylphenyl}morpholine,1-[3-fluoro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]-4-propylpiperazine,1-cyclopropylmethyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-1,2,3,6-tetrahydropyridine,1-butyl-4-{2-(3,3,4,4-tetramethylcyclopentyl)phenyl}piperazine,1-butyl-4-[2-(4,4-dimethylcyclohexyl)-4-(4-ethoxypiperidin-1-yl)phenyl]piperazine,1-butyl-4-[2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazine,1-cyclopropylmethyl-4-[2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazine,1-{4-[2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazin-1-yl}butan-2-one,1-(2-methoxyethyl)-4-[2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazine,1-{4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazin-1-yl}butan-2-one,1-(2-methoxyethyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine,4-[4-(4-butylpiperazin-1-yl)-5-(4,4-diethylcyclohexyl)-2-methoxyphenyl]-morpholine,1-butyl-4-(2-spiro[4.5]dec-8-ylphenyl)piperazine,1-[2-(4,4-dimethylcyclohex-1-enyl)phenyl]-4-isobutylpiperazine,1-cyclopropylmethyl-4-[2-(4,4-diethylcyclohexyl)-4-(4-methoxypiperidin-1-yl)phenyl]piperazine,4-[3-(4,4-dimethylcyclohexyl)-4-(4-isobutylpiperazin-1-yl)phenyl]morpholine,{4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazin-1-yl}acetonitrile,1-(2-ethoxyethyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine,(R)-1-butyl-4-[2-(4,4-diethylcyclohexyl)-4-(3-methoxypyrrolidin-1-yl)phenyl]piperazine,1-[4-methyl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-propylpiperazine,1-[4-methoxy-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-(tetrahydropyran-4-ylmethyl)piperazine,1-butyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperidine,1-isobutyl-4-[2-(3,3,4,4-tetramethylcyclopent-1-enyl)phenyl]piperazine,and1-[2-(4-cyclopropylmethylpiperazin-1-yl)phenyl]-3,3,5,5-tetramethylcyclohexanol.20. A medicament composition comprising the compound according to claim1 or 2, the salt thereof or the hydrate of the foregoing in associationwith a pharmaceutically acceptable additive.
 21. A cell adhesioninhibitor or cell infiltration inhibitor composition comprising thecompound according to claim 1 or 2, the salt thereof or the hydrate ofthe foregoing in association with a pharmaceutically acceptableadditive.
 22. A therapeutic composition for an inflammatory disease,comprising the compound according to claim 1 or 2, the salt thereof orthe hydrate of the foregoing in association with a pharmaceuticallyacceptable additive.
 23. A method of treating an inflammatory boweldisease, irritable bowel syndrome, rheumatoid arthritis, psoriasis,multiple sclerosis, asthma or atopic dermatitis in a patient, comprisingadministering to said patient a therapeutic composition containing thecompound according to claim 1 or 2, the salt thereof or the hydrate ofthe foregoing in association with a pharmaceutically acceptableadditive.
 24. A method of treating an inflammatory bowel disease in apatient, comprising administering to said patient a therapeuticcomposition containing the compound according to claim 1 or 2, the saltthereof or the hydrate of the foregoing in association with apharmaceutically acceptable additive.
 25. A method of treatingulcerative colitis or Crohn's disease in a patient, comprisingadministering to said patient a therapeutic composition containing thecompound according to claim 1 or 2, the salt thereof or the hydrate ofthe foregoing in association with a pharmaceutically acceptableadditive.